This application is the national phase under 35 U.S.C. xc2xa7371 of PCT International Application No. PCT/JP97/03595 which has an International filing date of Oct. 8, 1997 which designated the United States of America.
1. Technical Field
The present invention relates to a method for purifying pyruvic acid compounds.
2. Background Art
Pyruvic acid compounds are useful as intermediates for the synthesis of drugs or amino acids, and as disclosed in JP-A 55-81845, for example, they have been used as intermediates for the production of antihypertensives. Ethyl 7-halo-2-oxoheptanoate, which is also a pyruvic acid compound, is an important intermediate of cilastatin. For the production thereof, there has been known a process in which an organic magnesium compound is reacted with diethyl oxalate according to the following scheme 1 (see JP-A 58-77885). 
There has been known another process, for example, according to the following scheme 2, in which the synthesis is achieved by the reaction of a halide with ethyl 1,3-dithian-2-carboxylate and the subsequent deprotection [see J. Med. Chem., 30, 1074(1987)]. 
However, as described in the above references, the process according to scheme 1 has a defect in that the use of diethyl oxalate in excess makes the resulting pyruvic acid compound contaminated with diethyl oxalate and the process according to scheme 2 has a defect in that the use of a halide in excess and a base such as sodium hydride in mineral oil makes the resulting pyruvic acid compound contaminated with the halide and the mineral oil. Therefore, for obtaining pyruvic acid compounds, it requires the purification of intermediates or final pyruvic acid compounds by rectification or column chromatography.
For this reason, there has been sought a simple and easy method for purification by which the respective intermediates for synthesis or pyruvic acid compounds with high purity can be obtained without subjecting to a technique such as distillation or column chromatography.
Under these circumstances, the present inventors have intensively studied to develop a method in which pyruvic acid compounds can be purified by simple and easy procedures without using distillation, chromatography or any other techniques. As a result, they have found that the purification of a pyruvic acid compound can be achieved with high purity in a simple and easy manner by reacting the pyruvic acid compound with a bisulfite to give a bisulfite adduct of the pyruvic acid compound and then decomposing the adduct with an acid, thereby completing the present invention.
The present invention thus provides a method for purifying a pyruvic acid compound of general formula (I): 
wherein R1 is an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group, and R2 is an optionally substituted lower alkyl, which method is characterized in that the pyruvic acid compound of general formula (I) is reacted with a bisulfite of general formula (II):
MHSO3xe2x80x83xe2x80x83(II)
wherein M is NH4 or an alkali metal, to give a bisulfite adduct of the pyruvic acid compound and the adduct is then decomposed with an acid.
The present invention further provides a process for producing a pyruvic acid compound of general formula (VIII): 
wherein R3 is an optionally substituted lower alkyl group or an optionally substituted aryl group, and R4 is an optionally substituted lower alkyl group, with higher purity using the above purification method, as well as a bisulfite adduct of the pyruvic acid compound of general formula (VIII).
It seems that the adduct of the pyruvic acid compound of general formula (I) with the bisulfite of formula (II) according to the present invention may have a structure such as a sulfonic acid (e.g., the structure disclosed in Bull. Chem. Soc. Jpn., 40, 2703(1967)), a sulfurous acid ester, or a molecular compound (e.g., the structure described in JP-A 3-34948), similarly to the case of an adduct of an aldehyde with a bisulfite (see, e.g., xe2x80x9cDai-Yuhkikagaku (4th ed.)xe2x80x9d, vol. 3, pp. 56-57, published on Aug. 30, 1964, Asakura-shoten; J. Org. Chem., 6, 888(1941)). The adduct of the pyruvic acid compound of general formula (I) with the bisulfite of general formula (II) according to the present invention may include those having the structures in all these cases.
In the pyruvic acid compounds of general formula (I) according to the present invention, the optionally substituted lower alkyl group in the substituent R1 may include, for example, straight-chain or branched C1-C8 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, and n-octyl groups.
These alkyl groups may optionally be substituted with one to four substituents selected from halogen atoms, lower alkoxycarbonyl, lower alkoxy, optionally substituted aryloxy, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclic groups.
The halogen atoms as used herein may include fluorine, chlorine, bromine, and iodine atoms. In the following description, the halogen atoms have the same meaning as described above.
The lower alkoxycarbonyl groups may include, for example, straight-chain or branched C1-C6 alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, n-pentyloxycarbonyl, neopentyloxycarbonyl, and n-hexyloxycarbonyl groups.
The lower alkoxy groups may include, for example, straight-chain or branched C1-C6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, n-pentyloxy, neopentyloxy, and n-hexyloxy groups. In the following description, the lower alkoxy groups have the same meaning as described above.
The optionally substituted aryloxy groups may include, for example, phenoxy, 1-naphthyloxy, and 2-naphthyloxy groups.
The optionally substituted cycloalkyl groups may include, for example, cyclic C3-C8 alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
The optionally substituted aryl groups may include, for example, phenyl and naphthyl groups.
The optionally substituted heterocyclic groups may include, for example, monovalent groups of heterocycles containing one to three heteroatoms, such as furan, tetrahydrofuran, benzo[b]furan, pyrrole, pyrrolidine, pyridine, indole, imidazole, thiophene, and benzo[b]thiophene.
These aryloxy, cycloalkyl, aryl, and heterocyclic groups may optionally be further substituted with one to three substituents selected from halogen atoms, nitro, trifluoromethyl, lower alkyl, or lower alkoxy groups.
The lower alkyl groups as used herein may include, for example, straight-chain or branched C1-C6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and n-hexyl groups.
In the following description, the optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aryloxy, or optionally substituted heterocyclic groups have the same meaning as described above.
When the lower alkyl group in the substituent R1 is a methyl or ethyl group, it preferably has at least one substituent selected from halogen atoms, lower alkoxycarbonyl, lower alkoxy, optionally substituted aryloxy, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclic groups.
The optionally substituted lower alkenyl group in the substituent R1 may include, for example, straight-chain or branched C2-C6 alkenyl groups such as vinyl, 1-methylvinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-methyl-2-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl groups.
These alkenyl groups may optionally be substituted with one to four substituents selected from halogen atoms, lower alkoxy, optionally substituted aryloxy, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclic groups. When the lower alkenyl group in the substituent R1 is a vinyl group, it is preferably substituted as described above.
The optionally substituted lower alkynyl group in the substituent R1 may include, for example, straight-chain or branched C2-C6 alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 1-methyl-2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 4-methyl-2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl groups.
These alkynyl groups may optionally be substituted with one to four substituents selected from the same halogen atoms, lower alkoxy, optionally substituted aryloxy, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclic groups as described above. When the lower alkynyl group in the substituent R1 is an ethynyl group, it is preferably substituted as described above.
The optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclic groups in the substituent R1 may include the same groups as described above.
The optionally substituted lower alkyl group represented by substituent R2 may include, for example, straight-chain or branched C1-C6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and n-hexyl groups.
These lower alkyl groups may optionally be substituted with one to two optionally substituted aryl groups, and the aryl group may include, for example, phenyl and p-nitrophenyl groups. The lower alkyl groups substituted with the aryl group may include, for example, benzyl, p-nitrobenzyl, and 2-phenylethyl groups.
Specific examples of the pyruvic acid compound are methyl 3-cyclohexyl-2-oxopropanoate, methyl 3-(4-methoxycyclohexyl)-2-oxopropanoate, methyl 2-oxo-3-phenylpropanoate, methyl 3-(2-fluorophenyl)-2-oxopropanoate, methyl 3-(3-fluorophenyl)-2-oxopropanoate, methyl 3-(4-fluorophenyl)-2-oxopropanoate, methyl 3-(2-chlorophenyl)-2-oxopropanoate, methyl 3-(3-chlorophenyl)-2-oxopropanoate, methyl 3-(4-chlorophenyl)-2-oxopropanoate, methyl 3-(2-bromophenyl)-2-oxopropanoate, methyl 3-(3-bromophenyl)-2-oxopropanoate, methyl 3-(4-bromophenyl)-2-oxopropanoate, methyl 3-(2-iodophenyl)-2-oxopropanoate, methyl 3-(2,5-difluorophenyl)-2-oxopropanoate, methyl 3-(2,6-difluorophenyl)-2-oxopropanoate, methyl 3-(3,4-difluorophenyl)-2-oxopropanoate, methyl 3-(3,5-difluorophenyl)-2-oxopropanoate, methyl 3-(2,4-dichlorophenyl)-2-oxopropanoate, methyl 3-(2,6-dichlorophenyl)-2-oxopropanoate, methyl 3-(3,4-dichlorophenyl)-2-oxopropanoate, methyl 3-(2-chloro-6-fluorophenyl)-2-oxopropanoate, methyl 3-(2-nitrophenyl)-2-oxopropanoate, methyl 3-(3-nitrophenyl)-2-oxopropanoate, methyl 3-(4-nitrophenyl)-2-oxopropanoate, methyl 3-(2,4-dinitrophenyl)-2-oxopropanoate, methyl 3-(3,5-dinitrophenyl)-2-oxopropanoate, methyl 3-(4-chloro-2-nitrophenyl)-2-oxopropanoate, methyl 2-oxo-3-(2-trifluoromethylphenyl)propanoate, methyl 2-oxo-3-(3-trifluoromethylphenyl)propanoate, methyl 2-oxo-3-(4-trifluoromethylphenyl)propanoate, methyl 3-(3,5-bistrifluoromethylphenyl)-2-oxopropanoate, methyl 3-(2-methylphenyl)-2-oxopropanoate, methyl 3-(3-methylphenyl)-2-oxopropanoate, methyl 3-(4-methylphenyl)-2-oxopropanoate, methyl 3-(4-ethylphenyl)-2-oxopropanoate, methyl 3-(4-isopropylphenyl)-2-oxopropanoate, methyl 3-(4-t-butylphenyl)-2-oxopropanoate, methyl 3-(2,5-dimethylphenyl)-2-oxopropanoate, methyl 3-(3,4-dimethylphenyl)-2-oxopropanoate, methyl 3-(2-methyl-3-nitrophenyl)-2-oxopropanoate, methyl 3-(5-methyl-2-nitrophenyl)-2-oxopropanoate, methyl 2-oxo-3-(2,4,6-trimethylphenyl)propanoate, methyl 3-(2-methoxyphenyl)-2-oxopropanoate, methyl 3-(3-methoxyphenyl)-2-oxopropanoate, methyl 3-(4-methoxyphenyl)-2-oxopropanoate, methyl 3-(2-methoxy-5-nitrophenyl)-2-oxopropanoate, methyl 3-(1-naphthyl)-2-oxopropanoate, methyl 3-(2-naphthyl)-2-oxopropanoate, methyl 3-(3-indolyl)-2-oxopropanoate, methyl 3-methyl-2-oxobutanoate, methyl 3,3-dimethyl-2-oxobutanoate, methyl 4-methoxy-2-oxobutanoate, methyl 2-oxo-3-phenylbutanoate, methyl 3-methyl-2-oxo-4-phenylbutanoate, methyl 2-oxo-4-phenylbutanoate, methyl 4-(4-fluorophenyl)-2-oxobutanoate, methyl 4-(3-chlorophenyl)-2-oxobutanoate, methyl 4-(4-chlorophenyl)-2-oxobutanoate, methyl 4-(2-bromophenyl)-2-oxobutanoate, methyl 4-(2-nitrophenyl)- 2-oxobutanoate, methyl 4-(4-nitrophenyl)-2-oxobutanoate, methyl 4-(4-chloro-2-nitrophenyl)-2-oxobutanoate, methyl 4-(4-bromo-2-nitrophenyl)-2-oxobutanoate, methyl 2-oxo-4-(3-trifluoromethylphenyl)butanoate, methyl 4-(2-methylphenyl)-2-oxobutanoate, methyl 4-(2,4-dimethylphenyl)-2-oxobutanoate, methyl 4-(2-methoxyphenyl)-2-oxobutanoate, methyl 4-(4-methoxyphenyl)-2-oxobutanoate, methyl 4-(2,5-dimethoxyphenyl)-2-oxobutanoate, methyl 4-(3,4-dimethoxyphenyl)-2-oxobutanoate, methyl 4-(1-naphthyl)-2-oxobutanoate, methyl 4-(2-nitro-1-naphthyl)-2-oxobutanoate, methyl 4-(2-naphthyl)-2-oxobutanoate, methyl 4-(1-chloro-2-naphthyl)-2-oxobutanoate, methyl 4-(1-bromo-2-naphthyl)-2-oxobutanoate, methyl 4-(1-nitro-2-naphthyl)-2-oxobutanoate, methyl 2-oxopentanoate, methyl 3-methyl-2-oxopentanoate, methyl 5-cyclohexyl-2-oxopentanoate, methyl 2-oxo-5-phenylpentanoate, methyl 5-(3-chlorophenyl)-2-oxopentanoate, methyl 5-(3-methoxyphenyl)-2-oxopentanoate, methyl 5-(4-methoxyphenyl)-2-oxopentanoate, methyl 5,5-diphenyl-2-oxopentanoate, methyl 5-methoxy-2-oxo-5-phenylpentanoate, methyl 5-(4-chlorophenyl)-5-methoxy-2-oxopentanoate, methyl 5-isopropoxy-2-oxo-5-phenylpentanoate, methyl 5-isopropoxy-5-(4-methylphenyl)-2-oxopentanoate, methyl 2-oxo-5-phenoxypentanoate, methyl 5-(4-fluorophenoxy)-2-oxopentanoate, methyl 5-(2-bromo-4-methylphenoxy)-2-oxopentanoate, methyl 5-(2,6-dibromo-4-methylphenoxy)-2-oxopentanoate, methyl 2-oxohexanoate, methyl 5-methyl-2-oxohexanoate, methyl 5,5-dimethyl-2-oxohexanoate, methyl 2-oxo-5-phenylhexanoate, methyl 2-oxo-6-phenylhexanoate, methyl 2-oxo-6-phenoxyhexanoate, methyl 6-(2-methylphenoxy)-2-oxohexanoate, methyl 6-(3-methylphenoxy)-2-oxohexanoate, methyl 6-(4-methylphenoxy)-2-oxohexanoate, methyl 6-(4-nitrophenoxy)-2-oxohexanoate, methyl 6-(2,5-dimethylphenoxy)-2-oxohexanoate, methyl 2-oxoheptanoate, methyl 7-chloro-2-oxoheptanoate, methyl 7-bromo-2-oxoheptanoate, methyl 6-methyl-2-oxoheptanoate, methyl 2-oxo-7-phenylheptanoate, methyl 2-oxo-7-phenoxyheptanoate, methyl 7-(4-t-butylphenoxy)-2-oxoheptanoate, methyl 2-oxooctanoate, methyl 7-methyl-2-oxooctanoate, methyl 2-oxo-8-phenyloctanoate, methyl 2-oxononanoate, methyl 8-methyl-2-oxononanoate, methyl 2-oxodecanoate, methyl 2-oxo-10-phenoxydecanoate, methyl 3-methyl-2-oxo-3-butenoate, methyl 2-oxo-4-phenyl-3-butenoate, methyl 2-oxo-4-pentenoate, methyl 4-chloro-2-oxo-4-pentenoate, methyl 4-methyl-2-oxo-4-pentenoate, methyl 2-oxo-4-hexenoate, methyl 5-methyl-2-oxo-4-hexenoate, methyl 2-oxo-4-phenyl-3-butynoate, methyl 2-oxo-3-pentynoate, methyl 2-oxo-4-hexynoate, methyl 2-oxo-3-hexynoate, methyl 6-methoxy-2-oxo-3-hexynoate, methyl 7-ethoxy-2-oxo-3-heptynoate, methyl 2-cyclopropyl-2-oxoethanoate, methyl 2-cyclobutyl-2-oxoethanoate, methyl 2-cyclopentyl-2-oxoethanoate, methyl 2-cyclohexyl-2-oxoethanoate, methyl 2-cycloheptyl-2-oxoethanoate, methyl 2-cyclooctyl-2-oxoethanoate, methyl 2-oxo-2-phenylethanoate, methyl 2-(2-methylphenyl)-2-oxoethanoate, methyl 2-(4-methoxyphenyl)-2-oxoethanoate, methyl 2-(1-naphthyl)-2-oxoethanoate, methyl 2-(2-naphthyl)-2-oxoethanoate, methyl 2-(2-furyl)-2-oxoethanoate, methyl 2-(2-benzo[b]furyl)-2-oxoethanoate, methyl 2-oxo-2-(2-pyrrolyl)ethanoate, methyl 2-(3-indolyl)-2-oxoethanoate, methyl 2-oxo-2-(2-thienyl)ethanoate, methyl 2-(2-benzo[b]thienyl)-2-oxoethanoate, methyl 3-(benzothiazol-2-yl)-2-oxopropanoate, ethyl 3-cyclohexyl-2-oxopropanoate, ethyl 3-(4-methoxycyclohexyl)-2-oxopropanoate, ethyl 2-oxo-3-phenylpropanoate, ethyl 3-(2-fluorophenyl)-2-oxopropanoate, ethyl 3-(3-fluorophenyl)-2-oxopropanoate, ethyl 3-(4-fluorophenyl)-2-oxopropanoate, ethyl 3-(2-chlorophenyl)-2-oxopropanoate, ethyl 3-(3-chlorophenyl)-2-oxopropanoate, ethyl 3-(4-chlorophenyl)-2-oxopropanoate, ethyl 3-(2-bromophenyl)-2-oxopropanoate, ethyl 3-(3-bromophenyl)-2-oxopropanoate, ethyl 3-(4-bromophenyl)-2-oxopropanoate, ethyl 3-(2-iodophenyl)-2-oxopropanoate, ethyl 3-(2,5-difluorophenyl)-2-oxopropanoate, ethyl 3-(2,6-difluorophenyl)-2-oxopropanoate, ethyl 3-(3,4-difluorophenyl)-2-oxopropanoate, ethyl 3-(3,5-difluorophenyl)-2-oxopropanoate, ethyl 3-(2,4-dichlorophenyl)-2-oxopropanoate, ethyl 3-(2,6-dichlorophenyl)-2-oxopropanoate, ethyl 3-(3,4-dichlorophenyl)-2-oxopropanoate, ethyl 3-(2-chloro-6-fluorophenyl)-2-oxopropanoate, ethyl 3-(2-nitrophenyl)-2-oxopropanoate, ethyl 3-(3-nitrophenyl)-2-oxopropanoate, ethyl 3-(4-nitrophenyl)-2-oxopropanoate, ethyl 3-(2,4-dinitrophenyl)-2-oxopropanoate, ethyl 3-(3,5-dinitrophenyl)-2-oxopropanoate, ethyl 3-(4-chloro-2-nitrophenyl)-2-oxopropanoate, ethyl 2-oxo-3-(2-trifluoromethylphenyl)propanoate, ethyl 2-oxo-3-(3-trifluoromethylphenyl)propanoate, ethyl 2-oxo-3 -(4-trifluoromethylphenyl)propanoate, ethyl 3-(3,5-bistrifluoromethylphenyl)-2-oxopropanoate, ethyl 3-(2-methylphenyl)-2-oxopropanoate, ethyl 3-(3-methylphenyl)-2-oxopropanoate, ethyl 3-(4-methylphenyl)-2-oxopropanoate, ethyl 3-(4-ethylphenyl)-2-oxopropanoate, ethyl 3-(4-isopropylphenyl)-2-oxopropanoate, ethyl 3-(4-t-butylphenyl)-2-oxopropanoate, ethyl 3-(2,5-dimethylphenyl)-2-oxopropanoate, ethyl 3-(3,4-dimethylphenyl)-2-oxopropanoate, ethyl 3-(2-methyl-3-nitrophenyl)-2-oxopropanoate, ethyl 3-(5-methyl-2-nitrophenyl)-2-oxopropanoate, ethyl 2-oxo-3-(2,4,6-trimethylphenyl)propanoate, ethyl 3-(2-methoxyphenyl)-2-oxopropanoate, ethyl 3-(3-methoxyphenyl)-2-oxopropanoate, ethyl 3-(4-methoxyphenyl)-2-oxopropanoate, ethyl 3-(2-methoxy-5-nitrophenyl)-2-oxopropanoate, ethyl 3-(1-naphthyl)-2-oxopropanoate, ethyl 3-(2-naphthyl)-2-oxopropanoate, ethyl 3-(3-indolyl)-2-oxopropanoate, ethyl 3-methyl-2-oxobutanoate, ethyl 3,3-dimethyl-2-oxobutanoate, ethyl 4-methoxy-2-oxobutanoate, ethyl 2-oxo-3-phenylbutanoate, ethyl 3-methyl-2-oxo-4-phenylbutanoate, ethyl 2-oxo-4-phenylbutanoate, ethyl 4-(4-fluorophenyl)-2-oxobutanoate, ethyl 4-(3-chlorophenyl)-2-oxobutanoate, ethyl 4-(4-chlorophenyl)-2-oxobutanoate, ethyl 4-(2-bromophenyl)-2-oxobutanoate, ethyl 4-(2-nitrophenyl)-2-oxobutanoate, ethyl 4-(4-nitrophenyl)-2-oxobutanoate, ethyl 4-(4-chloro-2-nitrophenyl)-2-oxobutanoate, ethyl 4-(4-bromo-2-nitrophenyl)-2-oxobutanoate, ethyl 2-oxo-4-(3-trifluoromethylphenyl)butanoate, ethyl (2-methoxyphenyl)-2-oxobutanoate, ethyl 4-(2,4-dimethylphenyl)-2-oxobutanoate ethyl 4-(2-methoxyphenyl)-2-oxobutanoate, ethyl 4-(4-methoxyphenyl)-2-oxobutanoate, ethyl 4-(2,5-dimethoxyphenyl)-2-oxobutanoate, ethyl 4-(3,4-dimethoxyphenyl)-2-oxobutanoate, ethyl 4-(1-naphthyl)-2-oxobutanoate, ethyl 4-(2-nitro-1-naphthyl)-2-oxobutanoate, ethyl 4-(2-naphthyl)-2-oxobutanoate, ethyl 4-(1-chloro-2-naphthyl)-2-oxobutanoate, ethyl 4-(1-bromo-2-naphthyl)-2-oxobutanoate, ethyl 4-(1-nitro-2-naphthyl)-2-oxobutanoate, ethyl 2-oxopentanoate, ethyl 3-methyl-2-oxopentanoate, ethyl 2-oxopentanoate, ethyl 5-cyclohexyl-2-oxopentanoate, ethyl 2-oxo-5-phenylpentanoate, ethyl 5-(3-chlorophenyl)-2-oxopentanoate, ethyl 5-(3-methoxyphenyl)-2-oxopentanoate, ethyl 5-(4-methoxyphenyl)-2-oxopentanoate, ethyl 5,5-diphenyl-2-oxopentanoate, ethyl 5-methoxy-2-oxo-5-phenylpentanoate, ethyl 5-(4-chlorophenyl)-5-methoxy-2-oxopentanoate, ethyl 5-isopropoxy-2-oxo-5-phenylpentanoate, ethyl 5-isopropoxy-5-(4-methylphenyl)-2-oxopentanoate, ethyl 2-oxo-5-phenoxypentanoate, ethyl 5-(4-fluorophenoxy)-2-oxopentanoate, ethyl 5-(2-bromo-4-methylphenoxy)-2-oxopentanoate, ethyl 5-(2,6-dibromo-4-methylphenoxy)-2-oxopentanoate, ethyl 2-oxohexanoate, ethyl 5-methyl-2-oxohexanoate, ethyl 5,5-dimethyl-2-oxohexanoate, ethyl 2-oxo-5-phenylhexanoate, ethyl 2-oxo-6-phenylhexanoate, ethyl 2-oxo-6-phenoxyhexanoate, ethyl 6-(2-methylphenoxy)-2-oxohexanoate, ethyl 6-(3-methylphenoxy)-2-oxohexanoate, ethyl 6-(4-methylphenoxy)-2-oxohexanoate, ethyl 6-(4-nitrophenoxy)-2-oxohexanoate, ethyl 6-(2,5-dimethylphenoxy)-2-oxohexanoate, ethyl 2-oxoheptanoate, ethyl 7-chloro-2-oxoheptanoate, ethyl 7-bromo-2-oxoheptanoate, ethyl 6-methyl-2-oxoheptanoate, ethyl 2-oxo-7-phenylheptanoate, ethyl 2-oxo-7-phenoxyheptanoate, ethyl 7-(4-t-butylphenoxy)-2-oxoheptanoate, ethyl 2-oxooctanoate, ethyl 7-methyl-2-oxooctanoate, ethyl 2-oxo-8-phenyloctanoate, ethyl 2-oxononanoate, ethyl 8-methyl-2-oxononanoate, ethyl 2-oxodecanoate, ethyl 2-oxo-10-phenoxydecanoate, ethyl 3-methyl-2-oxo-3-butenoate, ethyl 2-oxo-4-phenyl-3-butenoate, ethyl 2-oxo-4-pentenoate, ethyl 4-chloro-2-oxo-4-pentenoate, ethyl 4-methyl-2-oxo-4-pentenoate, ethyl 2-oxo-4-hexenoate, ethyl 5-methyl-2-oxo-4-hexenoate, ethyl 2-oxo-4-phenyl-3-butynoate, ethyl 2-oxo-3-pentynoate, ethyl 2-oxo-4-hexynoate, ethyl 2-oxo-3-hexynoate, ethyl 6-methoxy-2-oxo-3-hexynoate, ethyl 7-ethoxy-2-oxo-3-heptynoate, ethyl 2-cyclopropyl-2-oxoethanoate, ethyl 2-cyclobutyl-2-oxoethanoate, ethyl 2-cyclopentyl-2-oxoethanoate, ethyl 2-cyclohexyl-2-oxoethanoate, ethyl 2-cycloheptyl-2-oxoethanoate, ethyl 2-cyclooctyl-2-oxoethanoate, ethyl 2-oxo-2-phenylethanoate, ethyl 2-(2-methylphenyl)-2-oxoethanoate, ethyl 2-(4-methoxyphenyl)-2-oxoethanoate, ethyl 2-(1-naphthyl)-2-oxoethanoate, ethyl 2-(2-naphthyl)-2-oxoethanoate, ethyl 2-(2-furyl)-2-oxoethanoate, ethyl 2-(2-benzo[b]furyl)-2-oxoethanoate, ethyl 2-oxo-2-(2-pyrrolyl)ethanoate, ethyl 2-(3-indolyl)-2-oxoethanoate, ethyl 2-oxo-2-(2-thienyl)ethanoate, ethyl 2-(2-benzo[b]thienyl)-2-oxoethanoate, ethyl 3-(benzothiazol-2-yl)-2-oxopropanoate, isopropyl 3-cyclohexyl-2-oxopropanoate, isopropyl 3-(4-methoxycyclohexyl)-2-oxopropanoate, isopropyl 2-oxo-3-phenylpropanoate, isopropyl 3-(2-fluorophenyl)-2-oxopropanoate, isopropyl 3-(3-fluorophenyl)-2-oxopropanoate, isopropyl 3-(4-fluorophenyl)-2-oxopropanoate, isopropyl 3-(2-chlorophenyl)-2-oxopropanoate, isopropyl 3-(3-chlorophenyl)-2-oxopropanoate, isopropyl 3-(4-chlorophenyl)-2-oxopropanoate, isopropyl 3-(2-bromophenyl)-2-oxopropanoate, isopropyl 3-(3-bromophenyl)-2-oxopropanoate, isopropyl 3-(4-bromophenyl)-2-oxopropanoate, isopropyl 3-(2-iodophenyl)-2-oxopropanoate, isopropyl 3-(2,5-difluorophenyl)-2-oxopropanoate, isopropyl 3-(2,6-difluorophenyl)-2-oxopropanoate, isopropyl 3-(3,4-difluorophenyl)-2-oxopropanoate, isopropyl 3-(3,5-difluorophenyl)-2-oxopropanoate, isopropyl 3-(2,4-dichlorophenyl)-2-oxopropanoate, isopropyl 3-(2,6-dichlorophenyl)-2-oxopropanoate, isopropyl 3-(3,4-dichlorophenyl)-2-oxopropanoate, isopropyl 3-(2-chloro-6-fluorophenyl)-2-oxopropanoate, isopropyl 3-(2-nitrophenyl)-2-oxopropanoate, isopropyl 3-(3-nitrophenyl)-2-oxopropanoate, isopropyl 3-(4-nitrophenyl)-2-oxopropanoate, isopropyl 3-(2,4-dinitrophenyl)-2-oxopropanoate, isopropyl 3-(3,5-dinitrophenyl)-2-oxopropanoate, isopropyl 3-(4-chloro-2-nitrophenyl)-2-oxopropanoate, isopropyl 2-oxo-3-(2-trifluoromethylphenyl)propanoate, isopropyl 2-oxo-3-(3-trifluoromethylphenyl)propanoate, isopropyl 2-oxo-3-(4-trifluoromethylphenyl)propanoate, isopropyl 3-(3,5-bistrifluoromethylphenyl)-2-oxopropanoate, isopropyl 3-(2-methylphenyl)-2-oxopropanoate, isopropyl 3-(3-methylphenyl)-2-oxopropanoate, isopropyl 3-(4-methylphenyl)-2-oxopropanoate, isopropyl 3-(4-ethylphenyl)-2-oxopropanoate, isopropyl 3-(4-isopropylphenyl)-2-oxopropanoate, isopropyl 3-(4-t-butylphenyl)-2-oxopropanoate, isopropyl 3-(2,5-dimethylphenyl)-2-oxopropanoate, isopropyl 3-(3,4-dimethylphenyl)-2-oxopropanoate, isopropyl 3-(2-methyl-3-nitrophenyl)-2-oxopropanoate, isopropyl 3-(5-methyl-2-nitrophenyl)-2-oxopropanoate, isopropyl 2-oxo-3-(2,4,6-trimethylphenyl)propanoate, isopropyl 3-(2-methoxyphenyl)-2-oxopropanoate, isopropyl 3-(3-methoxyphenyl)-2-oxopropanoate, isopropyl 3-(4-methoxyphenyl)-2-oxopropanoate, isopropyl 3-(2-methoxy-5-nitrophenyl)-2-oxopropanoate, isopropyl 3-(1-naphthyl)-2-oxopropanoate, isopropyl 3-(2-naphthyl)-2-oxopropanoate, isopropyl 3-(3-indolyl)-2-oxopropanoate, isopropyl 3-methyl-2-oxobutanoate, isopropyl 3,3-dimethyl-2-oxobutanoate, isopropyl 4-methoxy-2-oxobutanoate, isopropyl 2-oxo-3-phenylbutanoate, isopropyl 3-methyl-2-oxo-4-phenylbutanoate, isopropyl 2-oxo-4-phenylbutanoate, isopropyl 4-(4-fluorophenyl)-2-oxobutanoate, isopropyl 4-(3-chlorophenyl)-2-oxobutanoate, isopropyl 4-(4-chlorophenyl)-2-oxobutanoate, isopropyl 4-(2-bromophenyl)-2-oxobutanoate, isopropyl 4-(2-nitrophenyl)-2-oxobutanoate, isopropyl 4-(4-nitrophenyl)-2-oxobutanoate, isopropyl 4-(4-chloro-2-nitrophenyl)-2-oxobutanoate, isopropyl 4-(4-bromo-2-nitrophenyl)-2-oxobutanoate, isopropyl 2-oxo-4-(3-trifluoromethylphenyl)butanoate, isopropyl 4-(2-methylphenyl)-2-oxobutanoate, isopropyl 4-(2,4-dimethylphenyl)-2-oxobutanoate, isopropyl 4-(2-methoxyphenyl)-2-oxobutanoate, isopropyl 4-(4-methoxyphenyl)-2-oxobutanoate, isopropyl 4-(2,5-dimethoxyphenyl)-2-oxobutanoate, isopropyl 4-(3,4-dimethoxyphenyl)-2-oxobutanoate, isopropyl 4-(1-naphthyl)-2-oxobutanoate, isopropyl 4-(2-nitro-1-naphthyl)-2-oxobutanoate, isopropyl 4-(2-naphthyl)-2-oxobutanoate, isopropyl 4-(1-chloro-2-naphthyl)-2-oxobutanoate, isopropyl 4-(1-bromo-2-naphthyl)-2-oxobutanoate, isopropyl 4-(1-nitro-2-naphthyl)-2-oxobutanoate, isopropyl 2-oxopentanoate, isopropyl 3-methyl-2-oxopentanoate, isopropyl 2-oxopentanoate, isopropyl 5-cyclohexyl-2-oxopentanoate, isopropyl 2-oxo-5-phenylpentanoate, isopropyl 5-(3-chlorophenyl)-2-oxopentanoate, isopropyl 5-(3-methoxyphenyl)-2-oxopentanoate, isopropyl 5-(4-methoxyphenyl)-2-oxopentanoate, isopropyl 5,5-diphenyl-2-oxopentanoate, isopropyl 5-methoxy-2-oxo-5-phenylpentanoate, isopropyl 5-(4-chlorophenyl)-5-methoxy-2-oxopentanoate, isopropyl 5-isopropoxy-2-oxo-5-phenylpentanoate, isopropyl 5-isopropoxy-5-(4-methylphenyl)-2-oxopentanoate, isopropyl 2-oxo-5-phenoxypentanoate, isopropyl 5-(4-fluorophenoxy)-2-oxopentanoate, isopropyl 5-(2-bromo-4-methylphenoxy)-2-oxopentanoate, isopropyl 5-(2,6-dibromo-4-methylphenoxy)-2-oxopentanoate, isopropyl 2-oxohexanoate, isopropyl 5-methyl-2-oxohexanoate, isopropyl 5,5-dimethyl-2-oxohexanoate, isopropyl 2-oxo-5-phenylhexanoate, isopropyl 2-oxo-6-phenylhexanoate, isopropyl 2-oxo-6-phenoxyhexanoate, isopropyl 6-(2-methylphenoxy)-2-oxohexanoate, isopropyl 6-(3-methylphenoxy)-2-oxohexanoate, isopropyl 6-(4-methylphenoxy)-2-oxohexanoate, isopropyl 6-(4-nitrophenoxy)-2-oxohexanoate, isopropyl 6-(2,5-dimethylphenoxy)-2-oxohexanoate, isopropyl 2-oxoheptanoate, isopropyl 7-chloro-2-oxoheptanoate, isopropyl 7-bromo-2-oxoheptanoate, isopropyl 6-methyl-2-oxoheptanoate, isopropyl 2-oxo-7-phenylheptanoate, isopropyl 2-oxo-7-phenoxyheptanoate, isopropyl 7-(4-t-butylphenoxy)-2-oxoheptanoate, isopropyl 2-oxooctanoate, isopropyl 7-methyl-2-oxooctanoate, isopropyl 2-oxo-8-phenyloctanoate, isopropyl 2-oxononanoate, isopropyl 8-methyl-2-oxononanoate, isopropyl 2-oxodecanoate, isopropyl 2-oxo-10-phenoxydecanoate, isopropyl 3-methyl-2-oxo-3-butenoate, isopropyl 2-oxo-4-phenyl-3-butenoate, isopropyl 2-oxo-4-pentenoate, isopropyl 4-chloro-2-oxo-4-pentenoate, isopropyl 4-methyl-2-oxo-4-pentenoate, isopropyl 2-oxo-4-hexenoate, isopropyl 5-methyl-2-oxo-4-hexenoate, isopropyl 2-oxo-4-phenyl-3-butynoate, isopropyl 2-oxo-3-pentynoate, isopropyl 2-oxo-4-hexynoate, isopropyl 2-oxo-3-hexynoate, isopropyl 6-methoxy-2-oxo-3-hexynoate, isopropyl 7-ethoxy-2-oxo-3-heptynoate, isopropyl 2-cyclopropyl-2-oxoethanoate, isopropyl 2-cyclobutyl-2-oxoethanoate, isopropyl 2-cyclopentyl-2-oxoethanoate, isopropyl 2-cyclohexyl-2-oxoethanoate, isopropyl 2-cycloheptyl-2-oxoethanoate, isopropyl 2-cyclooctyl-2-oxoethanoate, isopropyl 2-oxo-2-phenylethanoate, isopropyl 2-(2-methylphenyl)-2-oxoethanoate, isopropyl 2-(4-methoxyphenyl)-2-oxoethanoate, isopropyl 2-(1-naphthyl)-2-oxoethanoate, isopropyl 2-(2-naphthyl)-2-oxoethanoate, isopropyl 2-(2-furyl)-2-oxoethanoate, isopropyl 2-(2-benzo[b]furyl)-2-oxoethanoate, isopropyl 2-oxo- 2-(2-pyrrolyl)ethanoate, osopropyl 2-(3-indolyl)-2-oxoethanoate, isopropyl 2-oxo-2-(2-thienyl)ethanoate, isopropyl 2-(2-benzo[b]thienyl)-2-oxoethanoate, isopropyl 3-(benzothiazol-2-yl)-2-oxopropanoate, benzyl 3-cyclohexyl-2-oxopropanoate, benzyl 3-(4-methoxycyclohexyl)-2-oxopropanoate, benzyl 2-oxo-3-phenylpropanoate, benzyl 3-(2-fluorophenyl)-2-oxopropanoate, benzyl 3-(3-fluorophenyl)-2-oxopropanoate, benzyl 3-(4-fluorophenyl)-2-oxopropanoate, benzyl 3-(2-chlorophenyl)-2-oxopropanoate, benzyl 3-(3-chlorophenyl)-2-oxopropanoate, benzyl 3-(4-chlorophenyl)-2-oxopropanoate, benzyl 3-(2-bromophenyl)-2-oxopropanoate, benzyl 3-(3-bromophenyl)-2-oxopropanoate, benzyl 3-(4-bromophenyl)-2-oxopropanoate, benzyl 3-(2-iodophenyl)-2-oxopropanoate, benzyl 3-(2,5-difluorophenyl)-2-oxopropanoate, benzyl 3-(2,6-difluorophenyl)-2-oxopropanoate, benzyl 3-(3,4-difluorophenyl)-2-oxopropanoate, benzyl 3-(3,5-difluorophenyl)-2-oxopropanoate, benzyl 3-(2,4-dichlorophenyl)-2-oxopropanoate, benzyl 3-(2,6-dichlorophenyl)-2-oxopropanoate, benzyl 3-(3,4-dichlorophenyl)-2-oxopropanoate, benzyl 3-(2-chloro-6-fluorophenyl)-2-oxopropanoate, benzyl 3-(2-nitrophenyl)-2-oxopropanoate, benzyl 3-(3-nitrophenyl)-2-oxopropanoate, benzyl 3-(4-nitrophenyl)-2-oxopropanoate, benzyl 3-(2,4-dinitrophenyl)-2-oxopropanoate, benzyl 3-(3,5-dinitrophenyl)-2-oxopropanoate, benzyl 3-(4-chloro-2-nitrophenyl)-2-oxopropanoate, benzyl 2-oxo-3-(2-trifluoromethylphenyl)propanoate, benzyl 2-oxo-3-(3-trifluoromethylphenyl)propanoate, benzyl 2-oxo-3-(4-trifluoromethylphenyl)propanoate, benzyl 3-(3,5-bistrifluoromethylphenyl)-2-oxopropanoate, benzyl 3-(2-methylphenyl)-2-oxopropanoate, benzyl 3-(3-methylphenyl)-2-oxopropanoate, benzyl 3-(4-methylphenyl)-2-oxopropanoate, benzyl 3-(4-ethylphenyl)-2-oxopropanoate, benzyl 3-(4-isopropylphenyl)-2-oxopropanoate, benzyl 3-(4-t-butylphenyl)-2-oxopropanoate, benzyl 3-(2,5-dimethylphenyl)-2-oxopropanoate, benzyl 3-(3,4-dimethylphenyl)-2-oxopropanoate, benzyl 3-(2-methyl-3-nitrophenyl)-2-oxopropanoate, benzyl 3-(5-methyl-2-nitrophenyl)-2-oxopropanoate, benzyl 2-oxo-3-(2,4,6-trimethylphenyl)propanoate, benzyl 3-(2-methoxyphenyl)-2-oxopropanoate, benzyl 3-(3-methoxyphenyl)-2-oxopropanoate, benzyl 3-(4-methoxyphenyl)-2-oxopropanoate, benzyl 3-(2-methoxy-5-nitrophenyl)-2-oxopropanoate, benzyl 3-(1-naphthyl)-2-oxopropanoate, benzyl 3-(2-naphthyl)-2-oxopropanoate, benzyl 3-(3-indolyl)-2-oxopropanoate, t-butyl 3-methyl-2-oxobutanoate, benzyl 3,3-dimethyl-2-oxobutanoate, benzyl 4-methoxy-2-oxobutanoate, benzyl 2-oxo-3-phenylbutanoate, benzyl 3-methyl-2-oxo-4-phenylbutanoate, benzyl 2-oxo-4-phenylbutanoate, benzyl 4-(4-fluorophenyl)-2-oxobutanoate, benzyl 4-(3-chlorophenyl)-2-oxobutanoate, benzyl 4-(4-chlorophenyl)-2-oxobutanoate, benzyl 4-(2-bromophenyl)-2-oxobutanoate, benzyl 4-(2-nitrophenyl)-2-oxobutanoate, benzyl 4-(4-nitrophenyl)-2-oxobutanoate, benzyl 4-(4-chloro-2-nitrophenyl)-2-oxobutanoate, benzyl 4-(4-bromo-2-nitrophenyl)-2-oxobutanoate, benzyl 4-(2-methylphenyl)-2-oxobutanoate, benzyl 2-oxo-4-(3-trifluoromethylphenyl)butanoate, benzyl 4-(2,4-dimethylphenyl)-2-oxobutanoate, benzyl 4-(2-methoxyphenyl)-2-oxobutanoate, benzyl 4-(4-methoxyphenyl)-2-oxobutanoate, benzyl 4-(2,5-dimethoxyphenyl)-2-oxobutanoate, benzyl 4-(3,4-dimethoxyphenyl)-2-oxobutanoate, benzyl 4-(1-naphthyl)-2-oxobutanoate, benzyl 4-(2-nitro-1-naphthyl)-2-oxobutanoate, benzyl 4-(2-naphthyl)-2-oxobutanoate, benzyl 4-(1-chloro-2-naphthyl)-2-oxobutanoate, benzyl 4-(1-bromo-2-naphthyl)-2-oxobutanoate, benzyl 4-(1-nitro-2-naphthyl)-2-oxobutanoate, benzyl 2-oxopentanoate, benzyl 3-methyl-2-oxopentanoate, benzyl 2-oxopentanoate, benzyl 5-cyclohexyl-2-oxopentanoate, benzyl 2-oxo-5-phenylpentanoate, benzyl 5-(3-chlorophenyl)-2-oxopentanoate, benzyl 5-(3-methoxyphenyl)-2-oxopentanoate, benzyl 5-(4-methoxyphenyl)-2-oxopentanoate, benzyl 5,5-diphenyl-2-oxopentanoate, benzyl 5-methoxy-2-oxo-5-phenylpentanoate, benzyl 5-(4-chlorophenyl)-5-methoxy-2-oxopentanoate, benzyl 5-isopropoxy-2-oxo-5-phenylpentanoate, benzyl 5-isopropoxy-5-(4-methylphenyl)-2-oxopentanoate, benzyl 2-oxo-5-phenoxypentanoate, benzyl 5-(4-fluorophenoxy-)-2-oxopentanoate, benzyl 5-(2-bromo-4-methylphenoxy)-2-oxopentanoate, benzyl 5-(2,6-dibromo-4-methylphenoxy)-2-oxopentanoate, benzyl 2-oxohexanoate, benzyl 5-methyl-2-oxohexanoate, benzyl 5,5-dimethyl-2-oxohexanoate, benzyl 2-oxo-5-phenylhexanoate, benzyl 2-oxo-6-phenylhexanoate, benzyl 2-oxo-6-phenoxyhexanoate, benzyl 6-(2-methylphenoxy)-2-oxohexanoate, benzyl 6-(3-methylphenoxy)-2-oxohexanoate, benzyl 6-(4-methylphenoxy)-2-oxohexanoate, benzyl 6-(4-nitrophenoxy)-2-oxohexanoate, benzyl 6-(2,5-dimethylphenoxy)-2-oxohexanoate, benzyl 2-oxoheptanoate, benzyl 7-chloro-2-oxoheptanoate, benzyl 7-bromo-2-oxoheptanoate, benzyl 6-methyl-2-oxoheptanoate, benzyl 2-oxo-7-phenylheptanoate, benzyl 2-oxo-7-phenoxyheptanoate, benzyl 7-(4-t-butylphenoxy)-2-oxoheptanoate, benzyl 2-oxooctanoate, benzyl 7-methyl-2-oxooctanoate, benzyl 2-oxo-8-phenyloctanoate, benzyl 2-oxononanoate, benzyl 8-methyl-2-oxononanoate, benzyl 2-oxodecanoate, benzyl 2-oxo-10-phenoxydecanoate, benzyl 3-methyl-2-oxo-3-butenoate, benzyl 2-oxo-4-phenyl-3-butenoate, benzyl 2-oxo-4-pentenoate, benzyl 4-chloro-2-oxo-4-pentenoate, benzyl 4-methyl-2-oxo-4-pentenoate, benzyl 2-oxo-4-hexenoate, benzyl 5-methyl-2-oxo-4-hexenoate, t-butyl 2-oxo-4-phenyl-3-butynoate, 2-oxo-3-pentynoate, benzyl 2-oxo-4-hexynoate, benzyl 2-oxo-3-hexynoate, benzyl 6-methoxy-2-oxo-3-hexynoate, benzyl 7-ethoxy-2-oxo-3-heptynoate, benzyl 2-cyclopropyl-2-oxoethanoate, benzyl 2-cyclobutyl-2-oxoethanoate, benzyl 2-cyclopentyl-2-oxoethanoate, benzyl 2-cyclohexyl-2-oxoethanoate, benzyl 2-cycloheptyl-2-oxoethanoate, benzyl 2-cyclooctyl-2-oxoethanoate, benzyl 2-oxo-2-phenylethanoate, benzyl 2-(2-methylphenyl)-2-oxoethanoate, benzyl 2-(4-methoxyphenyl)-2-oxoethanoate, benzyl 2-(1-naphthyl)-2-oxoethanoate, benzyl 2-(2-naphthyl)-2-oxoethanoate, benzyl 2-(2-furyl)-2-oxoethanoate, benzyl 2-(2-benzo[b]furyl)-2-oxoethanoate, benzyl 2-oxo-2-(2-pyrrolyl)ethanoate, benzyl 2-(3-indolyl)-2-oxoethanoate, benzyl 2-oxo-2-(2-thienyl)ethanoate, benzyl 2-(2-benzo [b]thienyl)-2-oxoethanoate, benzyl 3-(benzothiazol-2-yl)-2-oxopropanoate, propyl 2-oxo-4-phenylbutanoate, butyl 2-oxo-4-phenylbutanoate, isobutyl 2-oxo-4-phenylbutanoate, sec-butyl 2-oxo-4-phenylbutanoate, t-butyl 2-oxo-4-phenylbutanoate, pentyl 2-oxo-4-phenylbutanoate, neopentyl 2-oxo-4-phenylbutanoate, hexyl 2-oxo-4-phenylbutanoate, p-nitrobenzyl 2-oxo-4-phenylbutanoate, 2-phenylethyl 2-oxo-4-phenylbutanoate, t-butyl 4-(2-nitrophenyl)-2-oxobutanoate, dimethyl 1-oxopropane-1,3-dicarboxylate, diethyl 1-oxopropane-1,3-dicarboxylate, dibutyl 1-oxopropane-1,3-dicarboxylate, methyl 2,4-dioxo-4-phenylbutanoate, ethyl 2,4-dioxo-4-(2-thienyl)butanoate, methyl 2,4-dioxopentanoate, ethyl 2,4-dioxopentanoate, methyl 2,4-dioxo-5-phenylpentanoate, methyl 5,5-dimethyl-2,4-dioxohexanoate, ethyl 2,4-dioxo-6-phenyl-5-hexenoate, and butyl 2,4-dioxo-6-phenyl-5-hexenoate.
The bisulfite which can be used in the present invention may include ammonium hydrogensulfite, sodium hydrogensulfite, and potassium hydrogensulfite. The bisulfite may be a commercially available reagent or may be prepared by the absorption of sulfur dioxide gas into ammonia water or an aqueous solution of the corresponding alkali metal hydroxide.
The amount of bisulfite to be used is usually in the range of 0.3 to 10 times greater moles, preferably 0.5 to 5 times greater moles, relative to 1 mole of pyruvic acid compound (I).
The commercially available bisulfite may sometimes be a mixture of a bisulfite and a pyrosulfite. When such a mixture is used, it may be used in terms of the net mole amount of sulfurous acid contained in the mixture.
The net amount of sulfurous acid to be used when such a mixture is used is usually in the range of 0.3 to 10 times greater moles, preferably 0.5 to 5 times greater moles, relative to the pyruvic acid compound (I).
The method of the present invention is usually carried out by the use of water as a solvent. The amount of water to be used is usually in the range of 0.5 to 50 times greater by weight, preferably 1 to 30 times greater by weight, relative to the bisulfite. The use of an organic solvent is not particularly required; however, for achieving simpler and easier treatment after the reaction, water-insoluble or slightly-soluble organic solvents may be used in admixture with water.
The organic solvent is not particularly limited, so long as it is substantially inert to the reaction; and it may include, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as hexane, cyclohexane, and heptane; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, chloroform, and 1,2-dichlroroethane; ethers such as diethyl ether and diisopropyl ether; and ketones.
These solvents can be used each solely or in admixture of two or more kinds of solvents, and the amount of solvent to be used is usually in the range of 0.2 to 50 times greater by weight, preferably 0.5 to 30 times greater by weight, relative to the pyruvic acid compound (I).
The reaction of pyruvic acid compound (I) with bisulfite (II) in the present invention is carried out, for example, by supplying the pyruvic acid compound (I) dissolved in an organic solvent to an aqueous solution of the bisulfite. Alternatively, an aqueous solution of the bisulfite may also be supplied to the pyruvic acid compound (I) dissolved in an organic solvent. The reaction temperature is usually in the range ofxe2x88x925xc2x0 C. to 100xc2x0 C., preferably 0xc2x0 C. to 80xc2x0 C.
In the reaction, the pH of the reaction mixture can be controlled, if necessary. The pH controlling agent may include, for example, inorganic acids such as hydrochloric acid and sulfuric acid; organic acids such as oxalic acid, citric acid, and acetic acid; and inorganic bases such as sodium hydroxide and potassium hydroxide. The pH of the reaction mixture is preferably controlled in the range of 3 to 7, more preferably 3 to 6, by the addition of such a pH controlling agent.
The pH control is carried out, for example, by the addition of a pH controlling agent after an aqueous solution of the bisulfite is supplied to the pyruvic acid compound (I) dissolved in an organic solvent. Alternatively, the pyruvic acid compound (I) dissolved in an organic solvent may also be supplied to an aqueous solution of the bisulfite after a pH controlling agent is added to the aqueous solution of the bisulfite.
If necessary, phase transfer catalysts can be used. The phase transfer catalyst may include quaternary ammonium salts such as benzyltrimethylammonium chloride, benzyltriethylammonium chloride, tetrabutylammonium bromide, and tetrabutylammonium hydrogensulfate; and quaternary phosphonium salts such as triphenylphosphonium bromide and triphenylphosphonium iodide. The amount of phase transfer catalyst to be used is usually in the range of 0.005 to 0.8 time greater moles, preferably 0.01 to 0.2 time greater moles, relative to the pyruvic acid compound (I).
Thus, a bisulfite adduct of the pyruvic acid compound of general formula (I) can be obtained, and the bisulfite adduct may include, for example, those of the above-described pyruvic acid compound with ammonium hydrogensulfite, sodium hydrogensulfite or potassium hydrogensulfite.
The bisulfite adduct of the pyruvic acid compound (I) is obtained, for example, in the water layer by the phase separation of the reaction mixture after the reaction. In the phase separation, hydrophobic solvents or water may suitably be added, if necessary, before the phase separation, depending on the amount of water to be used in the reaction or the amount of organic solvent to be used in the reaction.
The hydrophobic solvent may include, for example, aromatic solvents such as benzene, toluene, and xylene; aliphatic solvents such as hexane, cyclohexane, and heptane; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, chloroform, and 1,2-dichloroethane; ketones such as methyl isobutyl ketone; and ethers such as diethyl ether and diisopropyl ether. The water layer can further be washed with a hydrophobic solvent to remove impurities with high efficiency.
From the water layer, the bisulfite adduct can easily be isolated, for example, by a technique such as solvent evaporation, and it can further be purified by a technique such as recrystallization.
By these procedures, organic compounds, which are contained in the pyruvic acid compound, but not reacted with the bisulfite to form an adduct, can be removed as impurities into the organic layer with high efficiency, so long as they are not mixed with water in any ratio.
After the reaction of the pyruvic acid compound (I) with the bisulfite, some portions of the pyruvic acid compound (I), if remaining unreacted, are recovered into the organic layer, and the unreacted portions of the pyruvic acid compound (I) in the organic layer can be reused in the step of reaction with an additional bisulfite. The bisulfite adduct specifically obtained may include those of the specific pyruvic acid compound as described above.
The subsequent decomposition of the bisulfite adduct of the pyruvic acid compound (I) with an acid can lead to the purification of the pyruvic acid compound (I).
As the acid, there is usually used an inorganic acid such as hydrochloric acid, sulfuric acid, or hydrobromic acid. The amount of acid to be used is usually in the range of 0.3 to 10 times greater moles, preferably 0.5 to 5 times greater moles, relative to the bisulfite adduct of the pyruvic acid compound (I).
The above decomposition is usually carried out by the use of water as a solvent. The amount of water to be used is usually in the range of 0.2 to 50 times greater by weight, preferably 0.5 to 30 times greater by weight, relative to the bisulfite adduct of the pyruvic acid compound (I).
The use of an organic solvent is not particularly required in the decomposition; however, for achieving simpler and easier treatment after the reaction, water-insoluble or slightly-soluble organic solvents can be used in admixture with water. The organic solvent is not particularly limited, so long as it is substantially inert to the reaction; and it may include, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as hexane, cyclohexane, and heptane; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, chloroform, and 1,2-dichlroroethane; ethers such as diethyl ether and diisopropyl ether; and ketones such as methyl isobutyl ketone.
These solvents can be used each solely or in admixture of two or more kinds of solvents, and the amount of solvent to be used is usually in the range of 0.2 to 50 times greater by weight, preferably 0.5 to 30 times greater by weight, relative to the pyruvic acid compound (I).
The decomposition with an acid is carried out, for example, by the addition of the acid to an aqueous solution of the bisulfite adduct of the pyruvic acid compound. The reaction temperature is usually 0xc2x0 C. to 100xc2x0 C., preferably 10xc2x0 C. to 80xc2x0 C.
The decomposition with an acid causes the evolution of sulfur dioxide gas, and the sulfur dioxide gas can be recovered as an aqueous solution of the bisulfite by the absorption into ammonia water or an aqueous solution of an alkali metal hydroxide. The recovered aqueous solution can be reused, if necessary, in the method of the present invention.
Thus, purified portions of the pyruvic acid compound (I) are produced, and the pyruvic acid compound (1) can easily be isolated, for example, from the organic layer after the phase separation of the reaction mixture, by an ordinary technique such as concentration under reduced pressure. In the phase separation, hydrophobic solvents or water may suitably be added, if necessary, before the phase separation, depending on the amount of water to be used in the reaction or the amount of organic solvent to be used in the reaction.
The hydrophobic solvent may include, for example, aromatic solvents such as benzene, toluene, and xylene; aliphatic solvents such as hexane, cyclohexane, and heptane; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, chloroform, and 1,2-dichloroethane; ketones such as methyl isobutyl ketone; and ethers such as diethyl ether and diisopropyl ether.
Specific examples of the pyruvic acid compound (I) thus obtained may include, as a matter of course, the same compounds as described above.
The pyruvic acid compound (I), which serves as the starting material in the present invention, can easily be produced, for example, from the corresponding organic metal compound in accordance with scheme 1 or from the corresponding halide in accordance with scheme 2.
Furthermore, the pyruvic acid compound (I) can also be produced, for example, in accordance with: (1) the process in which benzaldehyde and sodium pyruvate are condensed together to give benzalpyruvic acid, and the benzalpyruvic acid is then reacted with ethyl chloroformate to give ethyl benzalpyruvate, and the ethyl benzalpyruvate is then reduced [EP387058]; or (2) the process in which phenetyl bromide is reacted with carbon monoxide in the presence of a cobalt carbonyl catalyst [J. Mol. Cat., 88, 295(1994)]. The process for producing the pyruvic acid compound (I) as the starting material is not limited to these processes, either of which can be used as the production process for the starting material in the present invention.
In these pyruvic acid compounds, when R1 is R3(CH2)2xe2x80x94, the pyruvic acid compound of general formula (VIII) can be obtained by reacting an alkane compound of general formula (III): 
wherein R3 is an optionally substituted lower alkyl group or an optionally substituted aryl group, and X is a halogen atom or a sulfonyloxy group, with a xcex2-keto ester compound of general formula (IV): 
wherein R4 is an optionally substituted lower alkyl group, and R5 is an optionally substituted lower alkyl group or an optionally substituted lower alkoxy group, in the presence of a base, to give a diketo compound of general formula (V): 
wherein R3, R4, and R5 are as defined above; reacting the diketo compound of the general formula (V) with a nitrous acid compound of general formula (VI):
Yxe2x80x94Nxe2x95x90Oxe2x80x83xe2x80x83(VI)
wherein Y is a hydroxyl group, a lower alkoxy group, a halogen atom, or a xe2x80x94OSO3H group, to give an xcex1-oximino ester compound of general formula (VII): 
wherein R3 and R4 are as defined above; reacting the xcex1-oximino ester compound of general formula (VII) with an aldehyde compound in the presence of an acid to give a crude product of the pyruvic acid compound of general formula (VIII): 
wherein R3 and R4 are as defined above; reacting the crude product with a bisulfite of general formula (II):
MHSO3xe2x80x83xe2x80x83(II)
wherein M is NH4 or an alkali metal, to give a bisulfate adduct of the pyruvic acid compound; and decomposing the adduct with an acid.
In the alkane compound of general formula (III), the optionally substituted lower alkyl group in the substituent R3 may include, for example, straight-chain or branched C1-C6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and n-hexyl groups.
These lower alkyl groups may optionally be substituted with one to four substituents selected from halogen atoms, lower alkoxy, optionally substituted aryloxy, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclic groups.
These aryloxy, cycloalkyl, aryl, and heterocyclic groups may further be substituted with one to three substituents selected from halogen atoms, nitro, trifluoromethyl, lower alkyl or lower alkoxy groups. The lower alkyl group as used herein may include, for example, straight-chain or branched C1-C6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, an n-hexylm groups. The lower alkoxy group as used herein may include, for example, straight-chain or branched C1-C6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, neopentyloxy, and n-hexyloxy groups.
The optionally substituted aryl group in the substituent R3 may include, for example, phenyl and naphthyl groups. These aryl groups may optionally be substituted with one to three substituents selected from halogen atoms, nitro, trifluoromethyl, lower alkyl, or lower alkoxy groups. The lower alkyl group as used herein may include, for example, the same straight-chain or branched C1-C6 alkyl groups as described above. The lower alkoxy group as used herein may include, for example, the same straight-chain or branched C1-C6 alkoxy groups as described above.
The substituent X in the general formula (III) may include, for example, halogen atoms such as chlorine, bromine, and iodine atoms; and sulfonyloxy groups such as methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, and p-toluenesulfonyloxy groups.
The alkane compound may include, for example, 1-bromopropane, 1-cyclohexyl-3-bromopropane, 1-bromo-3-phenylpropane, 1-chloro-3-(4-chlorophenyl)propane, 1-bromo-3-(3-methoxyphenyl)propane, 1-bromo-3-(4-methoxyphenyl)propane, 1-bromo-3,3-diphenylpropane, 1-chloro-3-methoxy-3-phenylpropane, 1-chloro-3-(4-chlorophenyl)-3-methoxypropane, 1-chloro-3-isopropoxy-3-phenylpropane, 1-chloro-3-isopropoxy-3-(4-methylphenyl)propane, 1-bromo-3-phenoxypropane, 1-chloro-3-(4-fluorophenoxy)propane, 1-bromo-3-(2-bromo-4-methylphenoxy)propane, 1-bromo-3-(2,6-dibromo-4-methylphenoxy)propane, 1-bromobutane, 1-bromo-3-methylbutane, 1-bromo-3,3-dimethylbutane, 1-chloro-3-phenylbutane, 1-bromo-4-phenylbutane, 1-bromo-4-phenoxybutane, 1-chloro-4-(2-methylphenoxy)butane, 1-chloro-4-(3-methylphenoxy)butane, 1-chloro-4-(4-methylphenoxy)butane, 1-iodo-4-(4-nitrophenoxy)butane, 1-bromo-4-(2,5-dimethylphenoxy)butane, 1-bromopentane, 1,5-dichloropentane, 1-bromo-5-chloropentane, 1-chloro-5-iodopentane, 1,5-bromopentane, 1-bromo-5-iodopentane, 5-chloropentyl methanesulfonate, 5-chloropentyl p-toluenesulfonate, 1-bromo-4-methylpentane, 1-chloro-5-phenylpentane, 1-chloro-5-phenoxypentane, 1-bromo-5-(4-t-butylphenoxy)pentane, 1-bromohexane, 1-bromo-5-methylhexane, 1-bromo-6-phenylhexane, 1-bromoheptane, 1-bromo-6-methylheptane, 1-chlorooctane, 1-bromooctane, 1-iodooctane, octyl methanesulfonate, octyl trifluoromethanesulfonate, octyl benzenesulfonate, octyl p-toluenesulfonate, 1-bromo-8-phenoxyoctane, (2-chloroethyl)benzene, (2-bromoethyl)benzene, (2-iodoethyl)benzene, 2-phenylethyl methanesulfonate, 2-phenylethyl trifluoromethanesulfoante, 2-phenylethyl benzenesulfonate, 2-phenylethyl p-toluenesulfonate, 1-chloro-2-(4-fluorophenyl)ethane, 1-chloro-2-(3-chlorophenyl)ethane, 1-chloro-2-(4-chlorophenyl)ethane, 1-bromo-2-(2-bromophenyl)ethane, 1-chloro-2-(2-nitrophenyl)ethane, 1-bromo-2-(2-nitrophenyl)ethane, 1-bromo-2-(4-nitrophenyl)ethane, 1-chloro-2-(4-chloro-2-nitrophenyl)ethane, 1-bromo-2-(4-chloro-2-nitrophenyl)ethane, 1-(4-bromo-2-nitrophenyl)-2-chloroethane, 1-bromo-2-(4-bromo-2-nitrophenyl)ethane, 1-bromo-2-(3-trifluoromethylphenyl)ethane, 1-bromo-2-(2-methylphenyl)ethane, 1-bromo-2-(2,4-dimethylphenyl)ethane, 1-chloro-2-(2-methoxyphenyl)ethane, 1-bromo-2-(4-methoxyphenyl)ethane, 1-chloro-2-(2,5-dimethoxyphenyl)ethane, 1-(3,4-dimethoxyphenyl)-2-iodoethane, 1-bromo-2-(1-naphthyl)ethane, 1-bromo-2-(2-nitro-1-naphthyl)ethane, 1-bromo-2-(2-naphthyl)ethane, 1-bromo-2-(1-chloro-2-naphthyl)ethane, and 1-bromo-2-(1-bromo-2-naphthyl)ethane, 1-bromo-2-(1-nitro-2-naphthyl)ethane.
The alkane compound (I) can easily be synthesized from the corresponding alcohol, for example, in accordance with J. Am. Chem. Soc., 55, 4652(1933) or J. Med. Chem., 26, 947(1983), or from the corresponding carboxylic acid, for example, in accordance with J. Med. Chem., 20, 1020 (1977).
In the xcex2-keto ester compound of general formula (IV), the optionally substituted lower alkyl group represented by substituent R4 may include, for example, straight-chain or branched C1-C6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and n-hexyl groups. These alkyl groups may optionally be substituted with one to two optionally substituted aryl groups. The aryl group as used herein may include, for example, phenyl and p-nitrophenyl groups. The lower alkyl group substituted with the aryl group may include, for example, benzyl, p-nitrobenzyl, and 2-phenylethyl groups.
The lower alkyl group represented by substituent R5 in the general formula (IV) may include, for example, straight-chain or branched C1-C6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and n-hexyl groups.
The lower alkoxy group represented by substituent R5 may include, for example, straight-chain or branched C1-C6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, neopentyloxy, and n-hexyloxy.
When the substituent R5 is a lower alkoxy group or is represented by xe2x80x94OR6, R6 is preferably the same lower alkyl group as the lower alkyl group represented by R4.
The xcex2-keto ester compound may include, for example, methyl 3-oxobutanoate, ethyl 3-oxobutanoate, propyl 3-oxobutanoate, isopropyl 3-oxobutanoate, butyl 3-oxobutanoate, isobutyl 3-oxobutanoate, sec-butyl 3-oxobutanoate, t-butyl 3-oxobutanoate, pentyl 3-oxobutanoate, neopentyl 3-oxobutanoate, hexyl 3-oxobutanoate, benzyl 3-oxobutanoate, p-nitrobenzyl 3-oxobutanoate, 2-phenylethyl 3-oxobutanoate, methyl 3-oxopentanoate, ethyl 3-oxopentanoate, methyl 4-methyl-3-oxopentanoate, ethyl 4-methyl-3-oxopentanoate, methyl 4,4-dimethyl-3-oxopentanoate, ethyl 4,4-dimethyl-3-oxopentanoate, methyl 3-oxohexanoate, ethyl 3-oxohexanoate, ethyl 5-methyl-3-oxohexanoate, ethyl 3-oxoheptanoate, methyl 3-oxooctanoate, methyl 3-oxononanoate, dimethyl malonate, diethyl malonate, dipropyl malonate, diisopropyl malonate, dibutyl malonate, and di-t-butyl malonate. The amount of xcex2-keto ester compound to be used is usually in the range of 0.01 to 10 times greater moles, preferably 0.1 to 5 times greater moles, relative to the alkane compound.
The reaction is usually carried out in the presence of a base. The base may include, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium, t-butoxide; and hydroxides of alkali metals or alkaline earth metals, such as sodium hydroxide and calcium hydroxide. Preferably used is potassium carbonate. These bases are used each solely or in admixture of two or more kinds of bases, and the amount of base to be used is usually in the range of 0.8 to 20 times greater moles, preferably 0.9 to 10 times greater moles, relative to smaller one of the mole amounts of alkane compound (III) or xcex2-keto ester compound (IV) to be used.
The reaction may be carried out without solvent or may also be carried out by the use of a solvent. The solvent is not particularly limited, so long as it is substantially inert to the reaction; and it may include, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as hexane, cyclohexane, and heptane; halo-genated hydrocarbons such as chlorobenzene, dichlorobenzene, chloroform, and 1,2-dichloroethane; ethers such as diethyl ether and diisopropyl ether; ketones such as methyl isobutyl ketone; alcohols such as methanol, ethanol, and 2-propanol; amides such as N,N-dimethylformamide and N-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide; and nitrites such as acetonitrile.
When solvents are used, these solvents are used each solely or in admixture of two or more kinds of solvents, and the amount of solvent to be used is usually at most 50 times greater by weight, relative to the alkane compound (III).
When potassium carbonate is used as a base, it is preferred from the viewpoint of yield to control the total water content in the reaction system. The total water content in the reaction system is preferably controlled by the addition of water, if necessary, during the reaction so that it usually comes to 0.005 to 0.08 time greater by weight, preferably 0.005 to 0.05 time greater by weight, relative to the pure content of the potassium carbonate. When the potassium carbonate contains a small amount of water, the water content is preferably controlled, if necessary, so that it comes within the above range, taking into consideration the amount of water contained in the potassium carbonate.
In the reaction, phase transfer catalysts can be used, if necessary. The phase transfer catalyst may include, for example, quaternary ammonium salts such as benzyltrimethylammonium chloride, benzyltriethylammonium chloride, tetrabutylammonium bromide, and tetrabutylammonium hydrogensulfate; and quaternary phosphonium salts such as triphenylphosphonium bromide and triphenylphosphonium iodide. The amount of phase transfer catalyst to be used is usually in the range of 0.005 to 0.8 time greater moles, preferably 0.01 to 0.2 time greater moles, relative to the alkane compound (III).
The reaction is carried out, for example, by supplying a base into a mixture of alkane compound (III), xcex2-keto ester compound (IV), and a solvent. Alternatively, the xcex2-keto ester compound (IV) may also be supplied into a mixture of the alkane compound (III), the base, and the solvent; or the alkane compound (III) may also be supplied into a mixture of the xcex2-keto ester compound (IV), the base, and the solvent.
When potassium carbonate is used as a base, the reaction is carried out, for example, by supplying potassium carbonate into a mixture of alkane compound (III), xcex2-keto ester compound (IV), a solvent, and water. Alternatively, the xcex2-keto ester compound (IV) may also be supplied into a mixture of the alkane compound (III), potassium carbonate, the solvent, and water; or the alkane compound (III) may also be supplied into a mixture of the xcex2-keto ester compound (IV), potassium carbonate, the solvent, and water. Alternatively, the alkane compound (III), xcex2-ketoester compound (IV), potassium carbonate, and water have been all previously mixed, and the mixture may be controlled to a desired reaction temperature.
The reaction temperature is usually in the range of xe2x88x9250xc2x0 C. to 300xc2x0 C., preferably 0xc2x0 C. to 150xc2x0 C.
Thus, diketo compound (V) is produced, and the diketo compound (V) may be obtained in the organic layer, for example, by filtering the reaction mixture to give a filtrate, washing the filtered solid with a hydrophobic solvent to give a wash, and combining the filtrate and the wash into the organic layer. The hydrophobic solvent to be used for washing the filtered solid may include, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as hexane, cyclohexane, and heptane; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, chloroform, and 1,2-dichloroethane; ketones such as methyl isobutyl ketone; and ethers such as diethyl ether and diisopropyl ether. The filtration of the reaction mixture may be carried out after a hydrophobic solvent is suitably added depending on the amount of solvent to be used in the reaction. The hydrophobic solvent may include, for example, the same hydrophobic solvents as described above.
Alternatively, the organic layer can also be obtained, for example, by the addition of water to the reaction mixture to dissolve the solid and the subsequent phase separation of the mixture. When the amount of organic solvent to be used in the reaction is small, it may sometimes be difficult to easily achieve the phase separation, in which case, however, the addition of a suitable hydrophobic solvent may suitably be followed by the phase separation. The hydrophobic solvent may include, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as hexane, cyclohexane, and heptane; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, chloroform, and 1,2-dichloroethane; ketones such as methyl isobutyl ketone; and ethers such as diethyl ether and diisopropyl ether.
Thus, the diketo compound (V) containing organic layer is obtained. The diketo compound (V) can easily be isolated from the orgaLnic layer, for example, by a technique such as solvent evaporation, and it can be used in the next step without purification. Alternatively, the diketo compound (V) containing organic layer can also be used as such a solution in the next step without concentration.
Thus, the diketo compound of general formula (V) is obtained. The diketo compound may include, for example, methyl 3-oxo-2-(2-phenylethyl)butanoate, methyl 2-[(4-fluorophenyl)ethyl]-3-oxobutanoate, methyl 2-[(3-chlorophenyl)ethyl]-3-oxobutanoate, methyl 2-[(4-chlorophenyl)ethyl]-3-oxobutanoate, methyl 2-[(2-bromophenyl)ethyl]-3-oxobutanoate, methyl 2-[(2-nitrophenyl)ethyl]-3-oxobutanoate, methyl 2-[(4-nitrophenyl)ethyl]-3-oxobutanoate, methyl 2-[(4-chloro-2-nitrophenyl)ethyl]-3-oxobutanoate, methyl 2-[(4-bromo-2-nitrophenyl)ethyl]-3-oxobutanoate, methyl 3-oxo-2-[(3-trifluoromethylphenyl)ethyl]butanoate, methyl 2-[(2-methylphenyl)ethyl]-3-oxobutanoate, methyl 2-[(2,4-dimethylphenyl)ethyl]-3-oxobutanoate, methyl 2-[(2-methoxyphenyl)ethyl]-3-oxobutanoate, methyl 2-[(4-methoxyphenyl)ethyl]-3-oxobutanoate, methyl 2-[(2,5-dimethoxyphenyl)ethyl]-3-oxobutanoate, methyl 2-[(3,4-dimethoxyphenyl)ethyl]-3-oxobutanoate, methyl 2-[(1-naphthyl)ethyl]-3-oxobutanoate, methyl 2-[(2-nitro-1-naphthyl)ethyl]-3-oxobutanoate, methyl 2-[(2-naphthyl)ethyl]-3-oxobutanoate, methyl 2-[(1-chloro-2-naphthyl)ethyl]-3-oxobutanoate, methyl 2-[(1-bromo-2-naphthyl)ethyl]-3-oxobutanoate, methyl 2-[(1-nitro-2-naphthyl)ethyl]-3-oxobutanoate, methyl 2-(1-oxoethyl)pentanoate, methyl5-cyclohexyl-2-(1-oxoethyl)pentanoate, methyl 2-(1-oxoethyl)-5-phenylpentanoate, methyl 5-(3-chlorophenyl)-2-(1-oxoethyl)pentanoate, methyl 5-(3-methoxyphenyl)-2-(1-oxoethyl)pentanoate, methyl 5-(4-methoxyphenyl)-2-(1-oxoethyl)pentanoate, methyl 5,5-diphenyl-2-(1-oxoethyl)pentanoate, methyl 5-methoxy-2-(1-oxoethyl)-5-phenylpentanoate, methyl 5-(4-chlorophenyl)-5-methoxy-2-(1-oxoethyl)pentanoate, methyl 5-isopropoxy-2-(1-oxoethyl)-5-phenylpentanoate, methyl 5-isopropoxy-5-(4-methylphenyl)-2-(1-oxoethyl)pentanoate, methyl 2-(1-oxoethyl)-5-phenoxypentanoate, methyl 5-(4-fluorophenoxy)-2-(1-oxoethyl)pentanoate, methyl 5-(2-bromo-4-methylphenoxy)-2-(1-oxoethyl)pentanoate, methyl 5-(2,6-dibromo-4-methylphenoxy)-2-(1-oxoethyl)pentanoate, methyl 2-(1-oxoethyl)hexanoate, methyl 5-methyl-2-(1-oxoethyl)hexanoate, methyl 5,5-dimethyl-2-(1-oxoethyl)hexanoate, methyl 2-(1-oxoethyl)-5-phenylhexanoate, methyl 2-(1-oxoethyl)-6-phenylhexanoate, methyl 2-(1-oxoethyl)-6-phenoxyhexanoate, methyl 6-(2-methylphenoxy)-2-(1-oxoethyl)hexanoate, methyl 6-(3-methylphenoxy)-2-(1-oxoethyl)hexanoate, methyl 6-(4-methylphenoxy)-2-(1-oxoethyl)hexanoate, methyl 6-(4-nitrophenoxy)-2-(1-oxoethyl)hexanoate, methyl 6-(2,5-dimethylphenoxy)-2-(1-oxoethyl)hexanoate, methyl 2-(1-oxoethyl)heptanoate, methyl 7-chloro-2-(1-oxoethyl)heptanoate, methyl 7-bromo-2-(1-oxoethyl)heptanoate, methyl 6-methyl-2-(1-oxoethyl)heptanoate, methyl 2-(1-oxoethyl)-7-phenylheptanoate, methyl 2-(1-oxoethyl)-7-phenoxyheptanoate, methyl 7-(4-t-butylphenoxy)-2-(1-oxoethyl)heptanoate, methyl 2-(1-oxoethyl)octanoate, methyl 7-methyl-2-(1-oxoethyl)octanoate, methyl 2-(1-oxoethyl)-8-phenyloctanoate, methyl 2-(1-oxoethyl)nonanoate, methyl 8-methyl-2-(1-oxoethyl)nonanoate, methyl 2-(1-oxoethyl)decanoate, methyl 2-(1-oxoethyl)-10-phenoxydecanoate, ethyl 3-oxo-2-(2-phenylethyl)butanoate, ethyl 2-[(4-fluorophenyl)ethyl]-3-oxobutanoate, ethyl 2-[(3-chlorophenyl)ethyl]-3-oxobutanoate, ethyl 2-[(4-chlorophenyl)ethyl]-3-oxobutanoate, ethyl 2-[(2-bromophenyl)ethyl]-3-oxobutanoate, ethyl 2-[(2-nitrophenyl)ethyl]-3-oxobutanoate, ethyl 2-[(4-nitrophenyl)ethyl]-3-oxobutanoate, ethyl 2-[(4-chloro-2-nitrophenyl)ethyl]-3-oxobutanoate, ethyl 2-[(4-bromo-2-nitrophenyl)ethyl]-3-oxobutanoate, ethyl 3-oxo-2-[(3-trifluoromethylphenyl)ethyl]butanoate, ethyl 2-[(2-methylphenyl)ethyl]-3-oxobutanoate, ethyl 2-[(2,4-dimethylphenyl)ethyl]-3-oxobutanoate, ethyl 2-[(2-methoxyphenyl)ethyl]-3-oxobutanoate, ethyl 2-[(4-methoxyphenyl)ethyl]-3-oxobutanoate, ethyl 2-[(2,5-dimethoxyphenyl)ethyl]-3-oxobutanoate, ethyl 2-[(3,4-dimethoxyphenyl)ethyl]-3-oxobutanoate, ethyl 2-[(1-naphthyl)ethyl]-3-oxobutanoate, ethyl 2-[(2-nitro-1-naphthyl)ethyl]-3-oxobutanoate, ethyl 2-[(2phehyl)ethyl]-3-oxobutanoate, ethyl 2-[(1-chloro-2-naphthyl)ethyl]-3-oxobutanoate, -napthyl 2-[(1-bromo-2-naphthyl)ethyl]-3-oxobutanoate, ethyl 2-[(1-nitro-2-naphthyl)ethyl]-3-oxobutanoate, ethyl 2-(1-oxoethyl)pentanoate, ethyl 5-cyclohexyl-2-(1-oxoethyl)pentanoate, ethyl 2-(1-oxoethyl)-5-phenylpentanoate, ethyl 5-(3-chlorophenyl)-2-(1-oxoethyl)pentanoate, ethyl 5-(3-methoxyphenyl)-2-(1-oxoethyl)pentanoate, ethyl 5-(4-methoxyphenyl)-2-(1-oxoethyl)pentanoate, ethyl 5,5-diphenyl-2-(1-oxoethyl)pentanoate, ethyl 5-methoxy-2-(1-oxoethyl)-5-phenylpentanoate, ethyl 5-(4-chlorophenyl)-5-methoxy-2-(1-oxoethyl)pentanoate, ethyl 5-isopropoxy-2-(1-oxoethyl)-5-phenylpentanoate, ethyl 5-isopropoxy-5-(4-methylphenyl)-2-(1-oxoethyl)pentanoate, ethyl 2-(1-oxoethyl)-5-phenoxypentanoate, ethyl 5-(4-fluorophenoxy)-2-(1-oxoethyl)pentanoate, ethyl 5-(2-bromo-4-methylphenoxy)-2-(1-oxoethyl)pentanoate, ethyl 5-(2,6-dibromo-4-methylphenoxy)-2-(1-oxoethyl)pentanoate, ethyl 2-(1-oxoethyl)hexanoate, ethyl 5-methyl-2-(1-oxoethyl)hexanoate, ethyl 5,5-dimethyl-2-(1-oxoethyl)hexanoate, ethyl 2-(1-oxoethyl)-5-phenylhexanoate, ethyl 2-(1-oxoethyl)-6-phenylhexanoate, ethyl 2-(1-oxoethyl)-6-phenoxyhexanoate, ethyl 6-(2-methylphenoxy)-2-(1-oxoethyl)hexanoate, ethyl 6-(3-methylphenoxy)-2-(1-oxoethyl)hexanoate, ethyl 6-(4-methylphenoxy)-2-(1-oxoethyl)hexanoate, ethyl 6-(4-nitrophenoxy)-2-(1-oxoethyl)hexanoate, ethyl 6-(2,5-dimethylphenoxy)-2-(1-oxoethyl)hexanoate, ethyl 2-(1-oxoethyl)heptanoate, ethyl 7-chloro-2-(1-oxoethyl)heptanoate, ethyl 7-bromo-2-(1-oxoethyl)heptanoate, ethyl 6-methyl-2-(1-oxoethyl)petanoate, ethyl 2-(1-oxoethyl)-7-phenylheptanoate, ethyl 2-(1-oxoethyl)-7-phenoxyheptanoate, ethyl 7-(4-t-butylphenoxy)-2-(1-oxoethyl)heptanoate, ethyl 2-(1-oxoethyl)octanoate, ethyl 7-methyl-2-(1-oxoethyl)octanoate, ethyl 2-(1-oxoethyl)-8-phenyloctanoate, ethyl 2-(1-oxoethyl)nonanoate, ethyl 8-methyl-2-(1-oxoethyl)nonanoate, ethyl 2-(1-oxoethyl)decanoate, ethyl 2-(1-oxoethyl)-10-phenoxydecanoate, isopropyl 3-oxo-2-(2-phenylethyl)butanoate, isopropyl 2-[(4-fluorophenyl)ethyl]-3-oxobutanoate, isopropyl 2-[(3-chlorophenyl)ethyl]-3-oxobutanoate, isopropyl 2-[(4-chlorophenyl)ethyl]-3-oxobutanoate, isopropyl 2-[(2-bromophenyl)ethyl]-3-oxobutanoate, isopropyl 2-[(2-nitrophenyl)ethyl]-3-oxobutanoate, isopropyl 2-[(4-nitrophenyl)ethyl]-3-oxobutanoate, isopropyl 2-[(4-chloro-2-nitrophenyl)ethyl]-3-oxobutanoate, isopropyl 2-[(4-bromo-2-nitrophenyl)ethyl]-3-oxobutanoate, isopropyl 3-oxo-2-[(3-trifluoromethylphenyl)ethyl]butanoate, isopropyl 2-[(2-methylphenyl)ethyl]-3-oxobutanoate, isopropyl 2-[(2,4-dimethylphenyl)ethyl]-3-oxobutanoate, isopropyl 2-[(2-methoxyphenyl)ethyl]-3-oxobutanoate, isopropyl 2-[(4-methoxyphenyl)ethyl]-3-oxobutanoate, isopropyl 2-[(2,5-dimethoxyphenyl)ethyl]-3-oxobutanoate, isopropyl 2-[(3,4-dimethoxyphenyl)ethyl]-3-oxobutanoate, isopropyl 2-[(1-naphthyl)ethyl]-3-oxobutanoate, isopropyl 2-[(2-nitro-1-naphthyl)ethyl]-3-oxobutanoate, isopropyl 2-[(2-naphthyl)ethyl]-3-oxobutanoate, isopropyl 2-[(1-chloro-2-naphthyl)ethyl]-3-oxobutanoate, isopropyl 2-[(1-bromo-2-naphthyl)ethyl]-3-oxobutanoate, isopropyl 2-[(1-nitro-2-naphthyl)ethyl]-3-oxobutanoate, isopropyl 2-(1-oxoethyl)pentanoate, isoprpyl 5-cyclohexyl-2-(1-oxoethyl)pentanoate, isopropyl 2-(1-oxoethyl)-5-phenylpentanoate, isopropyl 5-(3-chlorophenyl)-2-(1-oxoethyl)pentanoate, isopropyl 5-(3-methoxyphenyl)-2-(1-oxoethyl)pentanoate, isopropyl 5-(4-methoxyphenyl)-2-(1-oxoethyl)pentanoate, isopropyl 5,5-diphenyl-2-(1-oxoethyl)pentanoate, isopropyl 5-methoxy-2-(1-oxoethyl)-5-phenylpentanoate, isopropyl 5-(4-chlorophenyl)-5-methoxy-2-(1-oxoethyl)pentanoate, isopropyl 5-isopropoxy-2-(1-oxoethyl)-5-phenylpentanoate, isopropyl 5-isopropoxy-5-(4-methylphenyl)-2-(1-oxoethyl)pentanoate, isopropyl 2-(1-oxoethyl)-5-phenoxypentanoate, isopropyl 5-(4-fluorophenoxy)-2-(1-oxoethyl)pentanoate, isopropyl 5-(2-bromo-4-methylphenoxy)-2-(1-oxoethyl)pentanoate, isopropyl 5-(2,6-dibromo-4-methylphenoxy)-2-(1-oxoethyl)pentanoate, isopropyl 2-(1-oxoethyl)hexanoate, isopropyl 5-methyl-2-(1-oxoethyl)hexanoate, isopropyl 5,5-dimethyl-2-(1-oxoethyl)hexanoate, isopropyl 2-(1-oxoethyl)-5-phenylhexanoate, isopropyl 2-(1-oxoethyl)-6-phenylhexanoate, isopropyl 2-(1-oxoethyl)-6-phenoxyhexanoate, isopropyl 6-(2-methylphenoxy)-2-(1-oxoethyl)hexanoate, isopropyl 6-(3-methylphenoxy)-2-(1-oxoethyl)hexanoate, isopropyl 6-(4-methylphenoxy)-2-(1-oxoethyl)hexanoate, isopropyl 6-(4-nitrophenoxy)-2-(1-oxoethyl)hexanoate, isopropyl 6-(2,5-dimethylphenoxy)-2-(1-oxoethyl)hexanoate, isopropyl 2-(1-oxoethyl)heptanoate, isopropyl 7-chloro-2-(1-oxoethyl)heptanoate, isopropyl 7-bromo-2-(1-oxoethyl)heptanoate, isopropyl 6-methyl-2-(1-oxoethyl)heptanoate, isopropyl 2-(1-oxoethyl)-7-phenylheptanoate, isopropyl 2-(1-oxoethyl)-7-phenoxyheptanoate, isopropyl 7-(4-t-butylphenoxy)-2-(1-oxoethyl)heptanoate, isopropyl 2-(1-oxoethyl)octanoate, isopropyl 7-methyl-2-(1-oxoethyl)octanoate, isopropyl 2-(1-oxoethyl)-8-phenyloctanoate, isopropyl 2-(1-oxoethyl)nonanoate, isopropyl 8-methyl-2-(1-oxoethyl)nonanoate, isopropyl 2-(1-oxoethyl)decanoate, isopropyl 2-(1-oxoethyl)-10-phenoxydecanoate, 3-oxo-2-(2-phenylethyl)butanoate, benzyl 2-[(4-fluorophenyl)ethyl]-3-oxobutanoate, benzyl 2-[(3-chlorophenyl)ethyl]-3-oxobutanoate, benzyl 2-[(4-chlorophenyl)ethyl]-3-oxobutanoate, benzyl 2-[(2-bromophenyl)ethyl]-3-oxobutanoate, benzyl 2-[(2-nitrophenyl)ethyl]-3-oxobutanoate, benzyl 2-[(4-nitrophenyl)ethyl]-3-oxobutanoate, benzyl 2-[(4-chloro-2-nitrophenyl)ethyl]-3-oxobutanoate, benzyl 2-[(4-bromo-2-nitrophenyl)ethyl]-3-oxobutanoate, benzyl 3-oxo-2-[(3-trifluoromethylphenyl)ethyl]butanoate, benzyl 2-[(2-methylphenyl)ethyl]-3-oxobutanoate, benzyl 2-[(2,4-dimethylphenyl)ethyl]-3-oxobutanoate, benzyl 2-[(2-methoxyphenyl)ethyl]-3-oxobutanoate, benzyl 2-[(4-methoxyphenyl)ethyl]-3-oxobutanoate, benzyl 2-[(2,5-dimethoxyphenyl)ethyl]-3-oxobutanoate, benzyl 2-[(3,4-dimethoxyphenyl)ethyl]-3-oxobutanoate, benzyl 2-[(1-naphthyl)ethyl]-3-oxobutaonoate, benzyl 2-[(2-nitro-1-naphthyl)ethyl]-3-oxobutanoate, benzyl 2-[(2-naphthyl)ethyl]-3-oxobutanoate, benzyl 2-[(1-chloro-2-naphthyl)ethyl]-3-oxobutanoate, benzyl 2-[(1-bromo-2-naphthyl)ethyl]-3-oxobutanoate, benzyl 2-[(1-nitro-2-naphthyl)ethyl]-3-oxobutanoate, benzyl 2-(1-oxoethyl)pentanoate, benzyl 5-cyclohexyl-2-(1-oxoethyl)pentanoate, benzyl 2-(1-oxoethyl)-5-phenylpentanoate, benzyl 5-(3-chlorophenyl)-2-(1-oxoethyl)pentanoate, benzyl 5-(3-methoxyphenyl)-2-(1-oxoethyl)pentanoate, benzyl 5-(4-methoxyphenyl)-2-(1-oxoethyl)pentanoate, benzyl 5,5-diphenyl-2-(1-oxoethyl)pentanoate, benzyl 5-methoxy-2-(1-oxoethyl)-5-phenylpentanoate, benzyl 5-(4-chlorophenyl)-5-methoxy-2-(1-oxoethyl)pentanoate, benzyl 5-isopropoxy-2-(1-oxoethyl)-5-phenylpentanoate, benzyl 5-isopropoxy-5-(4-methylphenyl)-2-(1-oxoethyl)pentanoate, benzyl 2-(1-oxoethyl)-5-phenoxypentanoate, benzyl 5-(4-fluorophenoxy)-2-(1-oxoethyl)pentanoate, benzyl 5-(2-bromo-4-methylphenoxy)-2-(1-oxoethyl)pentanoate, benzyl 5-(2,6-dibromo-4-methylphenoxy)-2-(1-oxoethyl)pentanoate, benzyl 2-(1-oxoethyl)hexanoate, benzyl 5-methyl-2-(1-oxoethyl)hexanoate, benzyl 5,5-dimethyl-2-(1-oxoethyl)hexanoate, benzyl 2-(1-oxoethyl)-5-phenylhexanoate, benzyl 2-(1-oxoethyl)-6-phenylhexanoate, benzyl 2-(1-oxoethyl)-6-phenoxyhexanoate, benzyl 6-(2-methylphenoxy)-2-(1-oxoethyl)hexanoate, benzyl 6-(3-methylphenoxy)-2-(1-oxoethyl)hexanoate, benzyl 6-(4-methylphenoxy)-2-(1-oxoethyl)hexanoate, benzyl 6-(4-nitrophenoxy)-2-(1-oxoethyl)hexanoate, benzyl 6-(2,5-dimethylphenoxy)-2-(1-oxoethyl)hexanoate, benzyl 2-(1-oxoethyl)heptanoate, benzyl 7-chloro-2-(1-oxoethyl)heptanoate, benzyl 7-bromo-2-(1-oxoethyl)heptanoate, benzyl 6-methyl-2-(1-oxoethyl)heptanoate, benzyl 2-(1-oxoethyl)-7-phenylheptanoate, benzyl 2-(1-oxoethyl)-7-phenoxyheptanoate, benzyl 7-(4-t-butylphenoxy)-2-(1-oxoethyl)heptanoate, benzyl 2-(1-oxoethyl)octanoate, benzyl 7-methyl-2-(1-oxoethyl)octanoate, benzyl 2-(1-oxoethyl)-8-phenyloctanoate, benzyl 2-(1-oxoethyl)nonanoate, benzyl 8-methyl-2-(1-oxoethyl)nonanoate, benzyl 2-(1-oxoethyl)decanoate, benzyl 2-(1-oxoethyl)-10-phenoxydecanoate, propyl 3-oxo-2-(2-phenylethyl)butanoate, butyl 3-oxo-2-(2-phenylethyl)butanoate, isobutyl 3-oxo-2-(2-phenylethyl)butanoate, sec-butyl 3-oxo-2-(2-phenylethyl)butanoate, t-butyl 3-oxo-2-(2-phenylethyl)butanoate, pentyl 3-oxo-2-(2-phenylethyl)butanoate, neopentyl 3-oxo-2-(2-phenylethyl)butanoate, hexyl 3-oxo-2-(2-phenylethyl)butanoate, p-nitrobenzyl 3-oxo-2-(2-phenylethyl)butanoate, 2-phenylethyl 3-oxo-2-(2-phenylethyl)butanoate, t-butyl 3-oxo-2-[2-(2-nitrophenyl)ethyl]butanoate, methyl 3-oxo-2-(2-phenylethyl)pentanoate, ethyl 3-oxo-2-(2-phenylethyl)pentanoate, methyl 4-methyl-3-oxo-2-(2-phenylethyl)pentanoate, ethyl 4-methyl-3-oxo-2-(2-phenylethyl)pentanoate, methyl 4,4-dimethyl-3-oxo-2-(2-phenylethyl)pentanoate, ethyl 4,4-dimethyl-3-oxo-2-(2-phenylethyl)pentanoate, methyl 3-oxo-2-(2-phenylethyl)hexanoate, ethyl 3-oxo-2-(2-phenylethyl)hexanoate, ethyl 5-methyl-3-oxo-2-(2-phenylethyl)hexanoate, ethyl 3-oxo-2-(2-phenylethyl)heptanoate, methyl 3-oxo-2-(2-phenylethyl)octanoate, methyl 3-oxo-2-(2-phenylethyl)nonanoate, dimethyl 6-chlorohexane-1,1-dicarboxylate, diethyl 6-chlorohexane-1,1-dicarboxylate, dimethyl 3-phenylpropane-1,1-dicarboxylate, diethyl 3-phenylpropane-1,1-dicarboxylate, diisopropyl 3-phenylpropane-1,1-dicarboxylate, di-t-butyl 3-phenylpropane-1,1-dicarboxylate, dimethyl 3-(2-nitrophenyl)propane-1,1-dicarboxylate, diethyl 3-(2-nitrophenyl)propane-1,1-dicarboxylate, dimethyl nonane-1,1-dicarboxylate, diethyl nonane-1,1-dicarboxylate, and diisopropyl nonane-1,1-dicarboxylate.
The diketo compound (V) obtained is then reacted with a nitrous acid compound of general formula (VI) to produce an cc-oximino ester compound of general formula (VII).
The halogen atom in the substituent Y in the general formula (VI) may include, for example, chlorine and bromine atoms. The lower alkoxy group may include, for example, straight-chain or branched C1-C6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, neopentyloxy, and n-hexyloxy.
The nitrous acid compound may include, for example, nitrous acid, methyl nitrite, ethyl nitrite, propyl nitrite, isopropyl nitrite, butyl nitrite, isobutyl nitrite, sec-butyl nitrite, t-butyl nitrite, pentyl nitrite, neopentyl nitrite, hexyl nitrite, nitrosyl chloride, and nitrosylsulfuric acid. The amount of nitrous acid compound to be used is usually in the range of 0.9 to 10 times greater moles, preferably 1 to 3 times greater moles, relative to the diketo compound (V).
The reaction is usually carried out in the presence of a base or an acid. When the reaction is carried out in the presence of a base, the base may include, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium t-butoxide; and hydrides of alkali metals or alkaline earth metals, such as sodium hydride and calcium hydride. These bases are used each solely or in admixture of two or more kinds of bases, and the amount of base to be used is usually in the range of 0.8 to 20 times greater moles, preferably 0.9 to 10 times greater moles, relative to the diketo compound (V).
When the reaction is carried out in the presence of an acid, the acid may include, for example, inorganic acids such as hydrogen chloride, hydrochloric acid, and sulfuric acid; and organic acids such as acetic acid, trifluoroacetic acid, and propionic acid. These acids are used each solely or in admixture of two or more kinds of acids, and the amount of acid to be used is usually in the range of 0.8 to 20 times greater moles, preferably 0.9 to 10 times greater moles, relative to the diketo compound (V).
The reaction can be carried out without solvent or can also be carried out in the presence of a solvent. The organic solvent is not particularly limited, so long as it is substantially inert to the reaction; and it may include, for example, alcohols such as water, methanol, ethanol, and isopropanol; aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as hexane, cyclohexane, and heptane; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, chloroform, and 1,2-dichloroethane; and ethers such as diethyl ether and diisopropyl ether. These solvents are used each solely or in admixture of two or more kinds of solvents, and the amount of solvent to be used is usually at most 50 times greater by weight, relative to the diketo compound (V).
When the reaction is carried out without solvent, it is achieved, for example, by supplying nitrous acid compound (VI) to a mixture of diketo compound (V) and an acid or a base. Alternatively, a mixture of the nitrous acid compound and the acid may also be supplied to the diketo compound. When the reaction is carried out in the presence of a solvent, it is achieved, for example, by supplying nitrous acid compound (VI) to a mixture of diketo compound (V) dissolved in an organic solvent and an acid or a base. Alternatively, a mixture of the nitrous acid compound and the acid may also be supplied to the diketo compound dissolved in an organic solvent. The reaction temperature is usually in the range of xe2x88x9250xc2x0 C. to 80xc2x0 C., preferably xe2x88x9230xc2x0 C. to 50xc2x0 C.
The xcex1-oximino ester compound may be obtained in the organic layer, for example, by pouring the reaction mixture after the reaction into water, followed by the extraction with an organic solvent. The organic solvent may include, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as hexane, cyclohexane, and heptane; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, chloroform, and 1,2-dichloroethane; ketones such as methyl isobutyl ketones; and ethers such as diethyl ether and diisopropyl ether.
The phase separation gives the xcex1-oximino ester compound (VII) containing organic layer. The xcex1-oximino ester compound (VII) can easily be isolated from the organic layer, for example, by a technique such as solvent evaporation, and it can be used in the next step without purification. Alternatively, the xcex1-oximino ester compound (VII) containing organic layer may also be used as such a solution in the next step without concentration. As a matter of course, the xcex1-oximino ester compound (VII) purified by an ordinary technique such as recrystallization or column chromatography can also be used in the next step.
Thus, the xcex1-oximino ester compound of general formula (VII) is obtained. The xcex1-oximino ester compound may include, for example, methyl 2-hydroximino-4-phenylbutanoate, methyl 4-(4-fluorophenyl)-2-hydroximinobutanoate, methyl 4-(3-chlorophenyl)-2-hydroximinobutanoate, methyl 4-(4-chlorophenyl)-2-hydroximinobutanoate, methyl 4-(2-bromophenyl)-2-hydroximinobutanoate, methyl 2-hydroximino-4-(2-nitrophenyl)butanoate, methyl 2-hydroximino-4-(4-nitrophenyl)butanoate, methyl 4-(4-chloro-2-nitrophenyl)-2-hydroximinobutanoate, methyl 4-(4-bromo-2-nitrophenyl)-2-hydroximinobutanoate, methyl 2-hydroximino-4-(3-trifluoromethylphenyl)butanoate, methyl 2-hydroximino-4-(2-methylphenyl)butanoate, methyl 4-(2,4-dimethylphenyl)-2-hydroximinobutanoate, methyl 2-hydroximino-4-(2-methoxyphenyl)butanoate, methyl 2-hydroximino-4-(4-methoxyphenyl)butanoate, methyl 4-(2,5-dimethoxyphenyl)-2-hydroximinobutanoate, methyl 4-(3,4-dimethoxyphenyl)-2-hydroximinobutanoate, methyl 2-hydroximino-4-(1-naphthyl)butanoate, methyl 2-hydroximino-4-(2-nitro-1-naphthyl)butanoate, methyl 2-hydroximino-4-(2-naphthyl)butanoate, methyl 4-(1-chloro-2-naphthyl)-2-hydroximinobutanoate, methyl 4-(1-bromo-2-naphthyl)-2-hydroximinobutanoate, methyl 2-hydroximino-4-(1-nitro-2-naphthyl)butanoate, methyl 2-hydroximinopentanoate, methyl 5-cyclohexyl-2-hydroximinopentanoate, methyl 2-hydroximino-5-phenylpentanoate, methyl 5-(3-chlorophenyl)-2-hydroximinopentanoate, methyl 2-hydroximino-5-(3-methoxyphenyl)pentanoate, methyl 2-hydroximino-5-(4-methoxyphenyl)pentanoate, methyl 5,5-diphenyl-2-hydroximinopentanoate, methyl 2-hydroximino-5-methoxy-5-phenylpentanoate, methyl 5-(4-chlorophenyl)-2-hydroximino-5-methoxypentanoate, methyl 2-hydroximino-5-isopropoxy-5-phenylpentanoate, methyl 2-hydroximino-5-isopropoxy-5-(4-methylphenyl)pentanoate, methyl 2-hydroximino-5-phenoxypentanoate, methyl 5-(4-fluorophenoxy)-2-hydroximinopentanoate, methyl 5-(2-bromo-4-methylphenoxy)-2-hydroximinopentanoate, methyl 5-(2,6-dibromo-4-methylphenoxy)-2-hydroximinopentanoate, methyl 2-hydroximinohexanoate, methyl 2-hydroximino-5-methylhexanoate, methyl 5,5-dimethyl-2-hydroximinohexanoate, methyl 2-hydroximino-5-phenylhexanoate, methyl 2-hydroximino-6-phenylhexanoate, methyl 2-hydroximino-6-phenoxyhexanoate, methyl 2-hydroximino-6-(2-methylphenoxy)hexanoate, methyl 2-hydroximino -6-(3-methylphenoxy)hexanoate, methyl 2-hydroximino-6-(4-methylphenoxy)hexanoate, methyl 2-hydroximino-6-(4-nitrophenoxy)hexanoate, methyl 6-(2,5-dimethylphenoxy)-2-hydroximinohexanoate, methyl 2-hydroximinoheptanoate, methyl 7-chloro-2-hydroximinoheptanoate, methyl 7-bromo-2-hydroximinoheptanoate, methyl 2-hydroximino-6-methylheptanoate, methyl 2-hydroximino-7-phenylheptanoate, methyl 2-hydroximino-7-phenoxyheptanoate, methyl 7-(4-t-butylphenoxy)-2-hydroximinoheptanoate, methyl 2-hydroximinooctanoate, methyl 2-hydroximino-7-methyloctanoate, methyl 2-hydroximino-8-phenyloctanoate, methyl 2-hydroximinononanoate, methyl 2-hydroximino-8-methylnonanoate, methyl 2-hydroximinodecanoate, methyl 2-hydroximino-10-phenoxydecanoate, ethyl 2-hydroximino-4-phenylbutanoate, ethyl 4-(4-fluorophenyl)-2-hydroximinobutanoate, ethyl 4-(3-chlorophenyl)-2-hydroximinobutanoate, ethyl 4-(4-chlorophenyl)-2-hydroximinobutanoate, ethyl 4-(2-bromophenyl)-2-hydroximinobutanoate, ethyl 2-hydroximino-4-(2-nitrophenyl)butanoate, ethyl 2-hydroximino-4-(4-nitrophenyl)butanoate, ethyl 4-(4-chloro-2-nitrophenyl)-2-hydroximinobutanoate, ethyl 4-(4-bromo-2-nitrophenyl)-2-hydroximinobutanoate, ethyl 2-hydroximino-4-(3-trifluoromethylphenyl)butanoate, ethyl 2-hydroximino-4-(2-methylphenyl)butanoate, ethyl 4-(2,4-dimethylphenyl)-2-hydroximinobutanoate, ethyl 2-hydroximino-4-(2-methoxyphenyl)butanoate, 2-hydroximino-4-(4-methoxyphenyl)butanoate, ethyl 4-(2,5-dimethoxyphenyl)-2-hydroximinobutanoate, ethyl 4-(3,4-dimethoxyphenyl)-2-hydroximinobutanoate, ethyl 2-hydroximino-4-(1-naphthyl)butanoate, ethyl 2-hydroximino-4-(2-nitro-1-naphthyl)butanoate, ethyl 2-hydroximino-4-(2-naphthyl)butanoate, ethyl 4-(1-chloro-2-naphthyl)-2-hydroximinobutanoate, ethyl 4-(1-bromo-2-naphthyl)-2-hydroximinobutanoate, ethyl 2-hydroximino-4-(1-nitro-2-naphthyl)butanoate, ethyl 2-hydroximinopentanoate, ethyl 5-cyclohexyl-2-hydroximinopentanoate, ethyl 2-hydroximino-5-phenylpentanoate, ethyl 5-(3-chlorophenyl)-2-hydroximinopentanoate, ethyl 2-hydroximino-5-(3-methoxyphenyl)pentanoate, ethyl 2-hydroximino-5-(4-methoxyphenyl)pentanoate, ethyl 5,5-diphenyl-2-hydroximinopentanoate, ethyl 2-hydroximino-5-methoxy-5-phenylpentanoate, ethyl 5-(4-chlorophenyl)-2-hydroximino-5-methoxypentanoate, ethyl 2-hydroximino-5-isopropoxy-5-phenylpentanoate, ethyl 2-hydroximino-5-isopropoxy-5-(4-methylphenyl)pentanoate, ethyl 2-hydroximino-5-phenoxypentanoate, ethyl 5-(4-fluorophenoxy)-2-hydroximinopentanoate, ethyl 5-(2-bromo-4-methylphenoxy)-2-hydroximinopentanoate, ethyl 5-(2,6-dibromo-4-methylphenoxy)-2-hydroximinopentanoate, ethyl 2-hydroximinohexanoate, ethyl 2-hydroximino-5-methylhexanoate, ethyl 5,5-dimethyl-2-hydroximinohexanoate, ethyl 2-hydroximino-5-phenylhexanoate, ethyl 2-hydroximino-6-phenylhexanoate, ethyl 2-hydroximino-6-phenoxyhexanoate, ethyl 2-hydroximino-6-(2-methylphenoxy)hexanoate, ethyl 2-hydroximino-6-(3-methylphenoxy)hexanoate, ethyl 2-hydroximino-6-(4-methylphenoxy)hexanoate, ethyl 2-hydroximino-6-(4-nitrophenoxy)hexanoate, ethyl 6-(2,5-dimethylphenoxy)-2-hydroximinohexanoate, ethyl 2-hydroximinoheptanoate, ethyl 7-chloro-2-hydroximinoheptanoate, ethyl 7-bromo-2-hydroximinoheptanoate, ethyl 2-hydroximino-6-methylheptanoate, ethyl 2-hydroximino-7-phenylheptanoate, ethyl 2-hydroximino-7-phenoxyheptanoate, ethyl 7-(4-t-butylphenoxy)-2-hydroximinoheptanoate, ethyl 2-hydroximinooctanoate, ethyl 2-hydroximino-7-methyloctanoate, ethyl 2-hydroximino-8-phenyloctanoate, ethyl 2-hydroximinononanoate, ethyl 2-hydroximino-8-methylnonanoate, ethyl 2-hydroximinodecanoate, ethyl 2-hydroximino-10-phenoxydecanoate, isopropyl 2-hydroximino-4-phenylbutanoate, isopropyl 4-(4-fluorophenyl)-2-hydroximinobutanoate, isopropyl 4-(3-chlorophenyl)-2-hydroximinobutanoate, isopropyl 4-(4-chlorophenyl)-2-hydroximinobutanoate, isopropyl 4-(2-bromophenyl)-2-hydroximinobutanoate, isopropyl 2-hydroximino-4-(2-nitrophenyl)butanoate, isopropyl 2-hydroximino-4-(4-nitrophenyl)butanoate, isopropyl 4-(4-chloro-2-nitrophenyl)-2-hydroximinobutanoate, isopropyl 4-(4-bromo-2-nitrophenyl)-2-hydroximinobutanoate, isopropyl 2-hydroximino-4-(3-trifluoromethylphenyl)butanoate, isopropyl 2-hydroximino-4-(2-methylphenyl)butanoate, isopropyl4-(2,4-dimethylphenyl)-2-hydroximinobutanoate, isopropyl 2-hydroximino-4-(2-methoxyphenyl)butanoate, isopropyl 2-hydroximino-4-(4-methoxyphenyl)butanoate, isopropyl 4-(2,5-dimethoxyphenyl)-2-hydroximinobutanoate, isopropyl 4-(3,4-dimethoxyphenyl)-2-hydroximinobutanoate, isopropyl 2-hydroximino-4-(1-naphthyl)butanoate, isopropyl 2-hydroximino-4-(2-nitro-1-naphthyl)butanoate, isopropyl 2-hydroximino-4-(2-naphthyl)butanoate, isopropyl 4-(1-chloro-2-naphthyl)-2-hydroximinobutanoate, isopropyl 4-(1-bromo-2-naphthyl)-2-hydroximinobutanoate, isopropyl 2-hydroximino-4-(1-nitro-2-naphthyl)butanoate, isopropyl 2-hydroximinopentanoate, isopropyl 5-cyclohexyl-2-hydroximinopentanoate, isopropyl 2-hydroximino-5-phenylpentanoate, isopropyl 5-(3-chlorophenyl)-2-hydroximinopentanoate, isopropyl 2-hydroximino-5-(3-methoxyphenyl)pentanoate, isopropyl 2-hydroximino-5-(4-methoxyphenyl)pentanoate, isopropyl 5,5-diphenyl-2-hydroximinopentanoate, isopropyl 2-hydroximino-5-methoxy-5-phenylpentanoate, isopropyl 5-(4-chlorophenyl)-2-hydroximino-5-methoxypentanoate, isopropyl 2-hydroximino-5-isopropoxy-5-phenylpentanoate, isopropyl 2-hydroximino-5-isopropoxy-5-(4-methylphenyl)pentanoate, isopropyl 2-hydroximino-5-phenoxypentanoate, isopropyl 5-(4-fluorophenoxy)-2-hydroximinopentanoate, isopropyl 5-(2-bromo-4-methylphenoxy)-2-hydroximinopentanoate, isopropyl 5-(2,6-dibromo-4-methylphenoxy)-2-hydroximinopentanoate, isopropyl 2-hydroximinohexanoate, isopropyl 2-hydroximino-5-methylhexanoate, isopropyl 5,5-dimethyl-2-hydroximinohexanoate, isopropyl 2-hydroximino-5-phenylhexanoate, isopropyl 2-hydroximino-6-phenylhexanoate, isopropyl 2-hydroximino-6-phenoxyhexanoate, isopropyl 2-hydroximino-6-(2-methylphenoxy)hexanoate, isopropyl 2-hydroximino-6-(3-methylphenoxy)hexanoate, isopropyl 2-hydroximino-6-(4-methylphenoxy)hexanoate, isopropyl 2-hydroximino-6-(4-nitrophenoxy)hexanoate, isopropyl 6-(2,5-dimethylphenoxy)-2-hydroximinohexanoate, isopropyl 2-hydroximinoheptanoate, isopropyl 7-chloro-2-hydroximinoheptanoate, isopropyl 7-bromo-2-hydroximinoheptanoate, isopropyl 2-hydroximino-6-methylheptanoate, isopropyl 2-hydroximino-7-phenylheptanoate, isopropyl 2-hydroximino-7-phenoxyheptanoate, isopropyl 7-(4-t-butylphenoxy)-2-hydroximinoheptanoate, isopropyl 2-hydroximinooctanoate, isopropyl 2-hydroximino-7-methyloctanoate, isopropyl 2-hydroximino-8-phenyloctanoate, isopropyl 2-hydroximinononanoate, isopropyl 2-hydroximino-8-methylnonanoate, isopropyl 2-hydroximinodecanoate, isopropyl 2-hydroximino-10-phenoxydecanoate, benzyl 2-hydroximino-4-phenylbutanoate, benzyl 4-(4-fluorophenyl)-2-hydroximinobutanoate, benzyl 4-(3-chlorophenyl)-2-hydroximinobutanoate, benzyl 4-(4-chlorophenyl)-2-hydroximinobutanoate, benzyl 4-(2-bromophenyl)-2-hydroximinobutanoate, benzyl 2-hydroximino-4-(2-nitrophenyl)butanoate, benzyl 2-hydroximino-4-(4-nitrophenyl)butanoate, benzyl 4-(4-chloro-2-nitrophenyl)-2-hydroximinobutanoate, benzyl 4-(4-bromo-2-nitrophenyl)-2-hydroximinobutanoate, benzyl 2-hydroximino-4-(3-trifluoromethylphenyl)butanoate, benzyl 2-hydroximino-4-(2-methylphenyl)butanoate, benzyl 4-(2,4-dimethylphenyl)-2-hydroximinobutanoate, benzyl 2-hydroximino-4-(2-methoxyphenyl)butanoate, benzyl 2-hydroximino-4-(4-methoxyphenyl)butanoate, benzyl 4-(2,5-dimethoxyphenyl)-2-hydroximinobutanoate, benzyl 4-(3,4-dimethoxyphenyl)-2-hydroximinobutanoate, benzyl 2-hydroximino-4-(1-naphthyl)butanoate, benzyl 2-hydroximino-4-(2-nitro-1-naphthyl)butanoate, benzyl 2-hydroximino-4-(2-naphthyl)butanoate, benzyl 4-(1-chloro-2-naphthyl)-2-hydroximinobutanoate, benzyl 4-(1-bromo-2-naphthyl)-2-hydroximinobutanoate, benzyl 2-hydroximino-4-(1-nitro-2-naphthyl)butanoate, benzyl 2-hydroximinopentanoate, benzyl 5-cyclohexyl-2-hydroximinopentanoate, benzyl 2-hydroximino-5-phenylpentanoate, benzyl 5-(3-chlorophenyl)-2-hydroximinopentanoate, benzyl 2-hydroximino-5-(3-methoxyphenyl)pentanoate, benzyl 2-hydroximino-5-(4-methoxyphenyl)pentanoate, benzyl 5,5-diphenyl-2-hydroximinopentanoate, benzyl 2-hydroximino-5-methoxy-5-phenylpentanoate, benzyl 5-(4-chlorophenyl)-2-hydroximino-5-methoxypentanoate, benzyl 2-hydroximino-5-isopropoxy-5-phenylpentanoate, benzyl 2-hydroximino-5-isopropoxy-5-(4-methylphenyl)pentanoate, benzyl 2-hydroximino-5-phenoxypentanoate, benzyl 5-(4-fluorophenoxy)-2-hydroximinopentanoate, benzyl 5-(2-bromo-4-methylphenoxy)-2-hydroximinopentanoate, benzyl 5-(2,6-dibromo-4-methylphenoxy)-2-hydroximinopentanoate, benzyl 2-hydroximinohexanoate, benzyl 2-hydroximino-5-methylhexanoate, benzyl 5,5-dimethyl-2-hydroximinohexanoate, benzyl 2-hydroximino-5-phenylhexanoate, benzyl 2-hydroximino-6-phenylhexanoate, benzyl 2-hydroximino-6-phenoxyhexanoate, benzyl 2-hydroximino-6-(2-methylphenoxy)hexanoate, benzyl 2-hydroximino-6-(3-methylphenoxy)hexanoate, benzyl 2-hydroximino-6-(4-methylphenoxy)hexanoate, benzyl 2-hydroximino-6-(4-nitrophenoxy)hexanoate, benzyl 6-(2,5-dimethylphenoxy)-2-hydroximinohexanoate, benzyl 2-hydroximinoheptanoate, benzyl 7-chloro-2-hydroximinoheptanoate, benzyl 7-bromo-2-hydroximinoheptanoate, benzyl 2-hydroximino-6-methylheptanoate, benzyl 2-hydroximino-7-phenylheptanoate, benzyl 2-hydroximino-7-phenoxyheptanoate, benzyl 7-(4-t-butylphenoxy)-2-hydroximinoheptanoate, benzyl 2-hydroximinooctanoate, benzyl 2-hydroximino-7-methyloctanoate, benzyl 2-hydroximino-8-phenyloctanoate, benzyl 2-hydroximinononanoate, benzyl 2-hydroximino-8-methylnonanoate, benzyl 2-hydroximinodecanoate, benzyl 2-hydroximino-10-phenoxydecanoate, propyl 2-hydroximino-4-phenylbutanoate, butyl 2-hydroximino-4-phenylbutanoate, isobutyl 2-hydroximino-4-phenylbutanoate, sec-butyl 2-hydroximino-4-phenylbutanoate, t-butyl 2-hydroximino-4-phenylbutanoate, pentyl 2-hydroximino-4-phenylbutanoate, neopentyl 2-hydroximino-4-phenylbutanoate, hexyl 2-hydroximino-4-phenylbutanoate, p-nitrobenzyl 2-hydroximino-4-phenylbutanoate, 2-phenylethyl 2-hydroximino-4-phenylbutanoate, and t-butyl 2-hydroximino-4-(2-nitrophenyl)butanoate.
The xcex1-oximino ester compound (VII) thus obtained is then reacted with an aldehyde compound in the presence of an acid to give the pyruvic acid compound (VIII).
As the acid, there is usually used an inorganic acid such as hydrochloric acid, sulfuric acid, or hydrobromic acid. The amount of acid to be used is usually at most 0.1 time greater moles, preferably in the range of 0.5 to 50 times greater moles, and more preferably in the range of 1 to 20 times greater moles, relative to the a-oximino ester compound (VII).
The aldehyde compound may include, for example, formaldehyde, formalin, paraformaldehyde, acetaldehyde, propionaldehyde, glyoxylic acid, and glyoxal.
The amount of aldehyde compound to be used is usually in the range of 0.8 to 15 times greater moles, preferably 0.9 to 10 times greater moles, relative to the a-oximino ester compound (VII).
The reaction is usually carried out in the presence of a solvent. The solvent is not particularly limited, so long as it is substantially inert to the reaction; and it may include, for example, water; aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as hexane, cyclohexane, and heptane; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, chloroform, and 1,2-dichloroethane; ethers such as diethyl ether and diisopropyl ether; ketones such as methyl isobutyl ketone; alcohols such as methanol, ethanol, and isopropanol; amides such as N,N-dimethylformamide and N-methyl-2-pyrrolidone; sulfoxides such as dimethylsulfoxide; and nitrites such as acetonitrile. These organic solvents are used each solely or in admixture of two or more kinds of solvents, and the amount of solvent to be used is usually in the range of 0.2 to 50 times greater by weight, preferably 0.5 to 30 times greater by weight, relative to the xcex1-oximino ester compound (VII).
The reaction is carried out, for example, by the addition of an aldehyde compound to a mixture of an a-oximino ester compound dissolved in an organic solvent with an acid. Alternatively, the acid may also be added to a mixture of the xcex1-oximino ester compound dissolved in an organic solvent with the aldehyde compound; or the xcex1-oximino ester compound dissolved in an organic solvent may also be added to a mixture of the aldehyde compound and the acid.
Furthermore, when the preceding step was carried out, for example, by the use of nitrosylsulfuric acid, the portion of the nitrosylsulfuric acid, which was consumed in the reaction, has become to sulfuric acid; therefore, the addition of an acid in this step is not particularly required, and for example, this step can be carried out, without separating the xcex1-oximino ester compound (VII) from the reaction mixture in the preceding step, by the addition thereof as such a mixture with the acid to the aldehyde compound.
The reaction temperature is usually in the range of xe2x88x9210xc2x0 C. to 100xc2x0 C., preferably 0 xc2x0 C. to 80xc2x0 C.
The pyruvic acid compound may be obtained in the organic layer, for example, by the phase separation of the reaction mixture. When the amount of water to be used in the reaction or the amount of organic solvent to be used in the reaction is small, it may sometimes be difficult to easily achieve the phase separation, in which case, however, the addition of a hydrophobic solvent or water may suitably be followed by the phase separation. The hydrophobic solvent may include, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as hexane, cyclohexane, and heptane; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, chloroform, and 1,2-dichloroethane; ketones such as methyl isobutyl ketone; and ethers such as diethyl ether and diisopropyl ether.
The phase separation gives the pyruvic acid compound (VIII) containing organic layer, and a crude product of the pyruvic acid compound (VIII) can easily be separated from the organic layer, for example, by a technique such as solvent evaporation, and it can be used for the starting material in the present invention. Alternatively, the pyruvic acid compound (VIII) containing organic layer can also be used as such a solution, without concentration, for the starting material in the present invention.
Thus, the pyruvic acid compound of general formula (VIII) is obtained. The pyruvic acid compound may include, for example, methyl 2-oxo-4-phenylbutanoate, methyl 4-(4-fluorophenyl)-2-oxobutanoate, methyl 4-(3-chlorophenyl)-2-oxobutanoate, methyl 4-(4-chlorophenyl)-2-oxobutanoate, methyl 4-(2-bromophenyl)-2-oxobutanoate, methyl 4-(2-nitrophenyl)-2-oxobutanoate, methyl 4-(4-nitrophenyl)-2-oxobutanoate, methyl 4-(4-chloro-2-nitrophenyl)-2-oxobutanoate, methyl 4-(4-bromo-2-nitrophenyl)-2-oxobutanoate, methyl 2-oxo-4-(3-trifluoromethylphenyl)butanoate, methyl 4-(2-methylphenyl)-2-oxobutanoate, methyl 4-(2,4-dimethylphenyl)-2-oxobutanoate, methyl 4-(2-methoxyphenyl)-2-oxobutanoate, methyl 4-(4-methoxyphenyl)-2-oxobutanoate, methyl 4-(2,5-dimethoxyphenyl)-2-oxobutanoate, methyl 4-(3,4-dimethoxyphenyl)-2-oxobutanoate, methyl 4-(1-naphthyl)-2-oxobutanoate, methyl 4-(2-nitro-1-naphthyl)-2-oxobutanoate, methyl 4-(2-naphthyl)-2-oxobutanoate, methyl 4-(1-chloro-2-naphthyl)-2-oxobutanoate, methyl 4-(1-bromo-2-naphthyl)-2-oxobutanoate, methyl 4-(1-nitro-2-naphthyl)-2-oxobutanoate, methyl 2-oxopentanoate, methyl 5-cyclohexyl-2-oxopentanoate, methyl 2-oxo-5-phenylpentanoate, methyl 5-(3-chlorophenyl)-2-oxopentanoate, methyl 5-(3-methoxyphenyl)-2-oxopentanoate, methyl 5-(4-methoxyphenyl)-2-oxopentanoate, methyl 5,5-diphenyl-2-oxopentanoate, methyl 5-methoxy-2-oxo-5-phenylpentanoate, methyl 5-(4-chlorophenyl)-5-methoxy-2-oxopentanoate, methyl 5-isopropoxy-2-oxo-5-phenylpentanoate, methyl 5-isopropoxy-5-(4-methylphenyl)-2-oxopentanoate, methyl 2-oxo-5-phenoxypentanoate, methyl 5-(4-fluorophenoxy)-2-oxopentanoate, methyl 5-(2-bromo-4-methylphenoxy)-2-oxopentanoate, methyl 5-(2,6-dibromo-4-methylphenoxy)-2-oxopentanoate, methyl 2-oxohexanoate, methyl 5-methyl-2-oxohexanoate, methyl 5,5-dimethyl-2-oxohexanoate, methyl 2-oxo-5-phenylhexanoate, methyl 2-oxo-6-phenylhexanoate, methyl 2-oxo-6-phenoxyhexanoate, methyl 6-(2-methylphenoxy)-2-oxohexanoate, methyl 6-(3-methylphenoxy)-2-oxohexanoate, methyl 6-(4-methylphenoxy)-2-oxohexanoate, methyl 6-(4-nitrophenoxy)-2-oxohexanoate, methyl 6-(2,5-dimethylphenoxy)-2-oxohexanoate, methyl 2-oxoheptanoate, methyl 7-chloro-2-oxoheptanoate, methyl 7-bromo-2-oxoheptanoate, methyl 6-methyl-2-oxoheptanote, methyl 2-oxo-7-phenylheptanoate, methyl 2-oxo-7-phenoxyheptanoate, methyl 7-(4-t-butylphenoxy)-2-oxoheptanoate, methyl 2-oxooctanoate, methyl 7-methyl-2-oxooctanoate, methyl 2-oxo-8-phenyloctanoate, methyl 2-oxononanoate, methyl 8-methyl-2-oxononanoate, methyl 2-oxodecanoate, methyl 2-oxo-10-phenoxydecanoate, ethyl 2-oxo-4-phenylbutanoate, ethyl 4-(4-fluorophenyl)-2-oxobutanoate, ethyl 4-(3-chlorophenyl)-2-oxobutanoate, ethyl 4-(4-chlorophenyl)-2-oxobutanoate, ethyl 4-(2-bromophenyl)-2-oxobutanoate, ethyl 4-(2-nitrophenyl)-2-oxobutanoate, ethyl 4-(4-nitrophenyl)-2-oxobutanoate, ethyl 4-(4-chloro-2-nitrophenyl)-2-oxobutanoate, ethyl 4-(4-bromo-2-nitrophenyl)-2-oxobutanoate, ethyl 2-oxo-4-(3-trifluoromethylphenyl)butanoate, ethyl (2-methylphehenyl)-2-oxobutanoate, ethyl 4-(2,4-dimethylphenyl)-2-oxobutanoate, ethyl 4-(2-methoxyphenyl)-2-oxobutanoate, ethyl 4-(4-methoxyphenyl)-2-oxobutanoate, ethyl 4-(2,5-dimethoxyphenyl)-2-oxobutanoate, ethyl 4-(3,4-dimethoxyphenyl)-2-oxobutanoate, ethyl 4-(1-naphthyl)-2-oxobutanoate, ethyl 4-(2-nitro-1-naphthyl)-2-oxobutanoate, ethyl 4-(2-naphthyl)-2-oxobutanoate, ethyl 4-(1-chloro-2-naphthyl)-2-oxobutanoate, ethyl 4-(1-bromo-2-naphthyl)-2-oxobutanoate, ethyl 4-(1-nitro-2-naphthyl)-2-oxobutanoate, ethyl 2-oxopentanoate, ethyl 5-cyclohexyl-2-oxopentanoate, ethyl 2-oxo-5-phenylpentanoate, ethyl 5-(3-chlorophenyl)-2-oxopentanoate, ethyl 5-(3-methoxyphenyl)-2-oxopentanoate, ethyl 5-(4-methoxyphenyl)-2-oxopentanoate, ethyl 5,5-diphenyl-2-oxopentanoate, ethyl 5-methoxy-2-oxo-5-phenylpentanoate, ethyl 5-(4-chlorophenyl)-5-methoxy-2-oxopentanoate, ethyl 5-isopropoxy-2-oxo-5-phenylpentanoate, ethyl 5-isopropoxy-5-(4-methylphenyl)-2-oxopentanoate, ethyl 2-oxo-5-phenoxypentanoate, ethyl 5-(4-fluorophenoxy)-2-oxopentanoate, ethyl 5-(2-bromo-4-methylphenoxy)-2-oxopentanoate, ethyl 5-(2,6-dibromo-4-methylphenoxy)-2-oxopentanoate, ethyl 2-oxohexanoate, ethyl 5-methyl-2-oxohexanoate, ethyl 5,5-dimethyl-2-oxohexanoate, ethyl 2-oxo-5-phenylhexanoate, ethyl 2-oxo-6-phenylhexanoate, ethyl 2-oxo-6-phenoxyhexanoate, ethyl 6-(2-methylphenoxy)-2-oxohexanoate, ethyl 6-(3-methylphenoxy)-2-oxohexanoate, ethyl 6-(4-methylphenoxy)-2-oxohexanoate, ethyl 6-(4-nitrophenoxy)-2-oxohexanoate, ethyl 6-(2,5-dimethylphenoxy)-2-oxohexanoate, ethyl 2-oxoheptanoate, ethyl 7-chloro-2-oxoheptanoate, ethyl 7-bromo-2-oxoheptanoate, ethyl 6-methyl-2-oxoheptanoate, ethyl 2-oxo-7-phenylheptanoate, ethyl 2-oxo-7-phenoxyheptanoate, ethyl 7-(4-t-butylphenoxy)-2-oxoheptanoate, ethyl 2-oxooctanoate, ethyl 7-methyl-2-oxooctanoate, ethyl 2-oxo-8-phenyloctanoate, ethyl 2-oxononanoate, ethyl 8-methyl-2-oxononanoate, ethyl 2-oxodecanoate, ethyl 2-oxo-10-phenoxydecanoate, isopropyl 2-oxo-4-phenylbutanoate, isopropyl 4-(4-fluorophenyl)-2-oxobutanoate, isopropyl 4-(3-chlorophenyl)-2-oxobutanoate, isopropyl 4-(4-chlorophenyl)-2-oxobutanoate, isopropyl 4-(2-bromophenyl)-2-oxobutanoate, isopropyl 4-(2-nitrophenyl)-2-oxobutanoate, isopropyl 4-(4-nitrophenyl)-2-oxobutanoate, isopropyl 4-(4-chloro-2-nitrophenyl)-2-oxobutanoate, isopropyl 4-(4-bromo-2-nitrophenyl)-2-oxobutanoate, isopropyl 2-oxo-4-(3-trifluoromethylphenyl)butanoate, isopropyl 4-(2-methylphenyl)-2-oxobutanoate, isopropyl 4-(2,4-dimethylphenyl)-2-oxobutanoate, isopropyl 4-(2-methoxyphenyl)-2-oxobutanoate, isopropyl 4-(4-methoxyphenyl)-2-oxobutanoate, isopropyl 4-(2,5-dimethoxyphenyl)-2-oxobutanoate, isopropyl 4-(3,4-dimethoxyphenyl)-2-oxobutanoate, isopropyl 4-(1-naphthyl)-2-oxobutanoate, isopropyl 4-(2-nitro-1-naphthyl)-2-oxobutanoate, isopropyl 4-(2-naphthyl)-2-oxobutanoate, isopropyl 4-(1-chloro-2-naphthyl)-2-oxobutanoate, isopropyl 4-(1-bromo-2-naphthyl)-2-oxobutanoate, isopropyl 4-(1-nitro-2-naphthyl)-2-oxobutanoate, isopropyl 2-oxopentanoate, isopropyl 5-cyclohexyl-2-oxopentanoate, isopropyl 2-oxo-5-phenylpentanoate, isopropyl 5-(3-chlorophenyl)-2-oxopentanoate, isopropyl 5-(3-methoxyphenyl)-2-oxopentanoate, isopropyl 5-(4-methoxyphenyl)-2-oxopentanoate, isopropyl 5,5-diphenyl-2-oxopentanoate, isopropyl 5-methoxy-2-oxo-5-phenylpentanoate, isopropyl 5-(4-chlorophenyl)-5-methoxy-2-oxopentanoate, isopropyl 5-isopropoxy-2-oxo-5-phenylpentanoate, isopropyl 5-isopropoxy-5-(4-methylphenyl)-2-oxopentanoate, isopropyl 2-oxo-5-phenoxypentanoate, isopropyl 5-(4-fluorophenoxy)-2-oxopentanoate, isopropyl 5-(2-bromo-4-methylphenoxy)-2-oxopentanoate, isopropyl 5-(2,6-dibromo-4-methylphenoxy)-2-oxopentanoate, isopropyl 2-oxohexanoate, isopropyl 5-methyl-2-oxohexanoate, isopropyl 5,5-dimethyl-2-oxohexanoate, isopropyl 2-oxo-5-phenylhexanoate, isopropyl 2-oxo-6-phenylhexanoate, isopropyl 2-oxo-6-phenoxyhexanoate, isopropyl 6-(2-methylphenoxy)-2-oxohexanoate, isopropyl 6-(3-methylphenoxy)-2-oxohexanoate, isopropyl 6-(4-methylphenoxy)-2-oxohexanoate, isopropyl 6-(4-nitrophenoxy)-2-oxohexanoate, isopropyl 6-(2,5-dimethylphenoxy)-2-oxohexanoate, isopropyl 2-oxoheptanoate, isopropyl 7-chloro-2-oxoheptanoate, isopropyl 7-bromo-2-oxoheptanoate, isopropyl 6-methyl-2-oxoheptanoate, isopropyl 2-oxo-7-phenylheptanoate, isopropyl 2-oxo-7-phenoxyheptanoate, isopropyl 7-(4-t-butylphenoxy)-2-oxoheptanoate, isopropyl 2-oxooctanoate, isopropyl 7-methyl-2-oxooctanoate, isopropyl 2-oxo-8-phenyloctanoate, isopropyl 2-oxononanoate, isopropyl 8-methyl-2-oxononanoate, isopropyl 2-oxodecanoate, isopropyl 2-oxo-10-phenoxydecanoate, benzyl 2-oxo-4-phenylbutanoate, benzyl 4-(4-fluorophenyl)-2-oxobutanoate, benzyl 4-(3-chlorophenyl)-2-oxobutanoate, benzyl 4-(4-chlorophenyl)-2-oxobutanoate, benzyl 4-(2-bromophenyl)-2-oxobutanoate, benzyl 4-(2-nitrophenyl)-2-oxobutanoate, benzyl 4-(4-nitrophenyl)-2-oxobutanoate, benzyl 4-(4-chloro-2-nitrophenyl)-2-oxobutanoate, benzyl 4-(4-bromo-2-nitrophenyl)-2-oxobutanoate, benzyl 4-(2-methylphenyl)-2-oxobutanoate, benzyl 2-oxo-4-(3-trifluoromethylphenyl)butanoate, benzyl 4-(2,4-dimethylphenyl)-2-oxobutanoate, benzyl 4-(2-methoxyphenyl)-2-oxobutanoate, benzyl 4-(4-methoxyphenyl)-2-oxobutanoate, benzyl 4-(2,5-dimethoxyphenyl)-2-oxobutanoate, benzyl 4-(3,4-dimethoxyphenyl)-2-oxobutanoate, benzyl 4-(1-naphthyl)-2-oxobutanoate, benzyl 4-(2-nitro-1-naphthyl)-2-oxobutanoate, benzyl 4-(2-naphthyl)-2-oxobutanoate, benzyl 4-(1-chloro-2-naphthyl)-2-oxobutanoate, benzyl 4-(1-bromo-2-naphthyl)-2-oxobutanoate, benzyl 4-(1-nitro-2-naphthyl)-2-oxobutanoate, benzyl 2-oxopentanoate, benzyl 5-cyclohexyl-2-oxopentanoate, benzyl 2-oxo-5-phenylpentanoate, benzyl 5-(3-chlorophenyl)-2-oxopentanoate, benzyl 5-(3-methoxyphenyl)-2-oxopentanoate, benzyl 5-(4-methoxyphenyl)-2-oxopentanoate, benzyl 5,5-diphenyl-2-oxopentanoate, benzyl 5-methoxy-2-oxo-5-phenylpentanoate, benzyl 5-(4-chlorophenyl)-5-methoxy-2-oxopentanoate, benzyl 5-isopropoxy-2-oxo-5-phenylpentanoate, benzyl 5-isopropoxy-5-(4-methylphenyl)-2-oxopentanoate, benzyl 2-oxo-5-phenoxypentanoate, benzyl 5-(4-fluorophenoxy)-2-oxopentanoate, benzyl 5-(2-bromo-4-methylphenoxy)-2-oxopentanoate, benzyl 5-(2,6-dibromo-4-methylphenoxy)-2-oxopentanoate, benzyl 2-oxohexanoate, benzyl 5-methyl-2-oxohexanoate, benzyl 5,5-dimethyl-2-oxohexanoate, benzyl 2-oxo-5-phenylhexanoate, benzyl 2-oxo-6-phenylhexanoate, benzyl 2-oxo-6-phenoxyhexanoate, benzyl 6-(2-methylphenoxy)-2-oxohexanoate, benzyl 6-(3-methylphenoxy)-2-oxohexanoate, benzyl 6-(4-methylphenoxy)-2-oxohexanoate, benzyl 6-(4-nitrophenoxy)-2-oxohexanoate, benzyl 6-(2,5-dimethylphenoxy)-2-oxohexanoate, benzyl 2-oxoheptanoate, benzyl 7-chloro-2-oxoheptanoate, benzyl 7-bromo-2-oxoheptanoate, benzyl 6-methyl-2-oxoheptanoate, benzyl 2-oxo-7-phenylheptanoate, benzyl 2-oxo-7-phenoxyheptanoate, benzyl 7-(4-t-butylphenoxy)-2-oxoheptanoate, benzyl 2-oxooctanoate, benzyl 7-methyl-2-oxooctanoate, benzyl 2-oxo-8-phenyloctanoate, benzyl 2-oxononanoate, benzyl 8-methyl-2-oxononanoate, benzyl 2-oxodecanoate, benzyl 2-oxo-10-phenoxydecanoate, propyl 2-oxo-4-phenylbutanoate, butyl 2-oxo-4-phenylbutanoate, isobutyl 2-oxo-4-phenylbutanoate, sec-butyl 2-oxo-4-phenylbutanoate, t-butyl 2-oxo-4-phenylbutanoate, pentyl 2-oxo-4-phenylbutanoate, neopentyl 2-oxo-4-phenylbutanoate, hexyl 2-oxo-4-phenylbutanoate, p-nitrobenzyl 2-oxo-4-phenylbutanoate, 2-phenylethyl 2-oxo-4-phenylbutanoate, and t-butyl 4-(2-nitrophenyl)-2-oxobutanoate.
The adduct of a pyruvic acid compound with a bisulfite, which adduct is obtained by subjecting the crude product of pyruvic acid compound (VIII) thus obtained to the purification method of the present invention, may include bisulfite adducts of the above pyruvic acid compounds (VIII). The pyruvic acid compounds can be simply and easily purified by the purification of the bisulfite adducts obtained. The production process makes it possible to achieve the production of pyruvic acid compounds (VIII) with higher purity without purifying any intermediate in the production of the pyruvic acid compounds (VIII) that serve as the starting material, and hence, it was advantageous from an industrial point of view.
Furthermore, the bisulfite adducts of pyruvic acid compounds (VIII) produced by the present invention are novel compounds, and the use of these bisulfite adducts makes it possible to produce pyruvic acid compounds (VIII) with higher purity, which compounds are useful as intermediates for drugs, xcex1-amino acids, or other products.